Amide derivatives

ABSTRACT

The invention concerns amide derivatives of Formula (Ia) wherein X is —NHCO— or —CONH—; m is 0–3; R 1  is a group such as hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy and carbamoyl; n is 0–2; R 2  is a group such as hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino and carboxy; R 3  is hydrogen, halogeno, (1–6C)alkyl or (1–6C)alkoxy. q is 0–4; and Q is a group such as aryl, aryloxy, aryl—(1–6C)alkoxy, arylamino and N—(1–6C)alkyl-arylamino; or pharmaceutically-acceptable salts or in-vivo-cleavable caters thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical conditions mediated by cytokines.

This application is the National Phase of International ApplicationPCT/GB/00/00912 filed Mar. 13, 2000 which designated the U.S. and thatInternational Application.

This invention concerns certain amide derivatives which are useful asinhibitor of cytokine mediated disease. The invention also concernsprocesses for the manufacture of the amide derivatives of the invention,pharmaceutical compositions containing them and their use in therapeuticmethods, for example by virtue of inhibition of cytokine mediateddisease.

The amide derivatives disclosed in the present invention are inhibitorsof the production of cytokines such as Tumour Necrosis Factor(hereinafter TNF), for example TNFα, and various members of theinterleukin (hereinafter IL) family, for example IL-1, IL-6 and IL-8.Accordingly the compounds of the invention will be useful in thetreatment of diseases or medical conditions in which excessiveproduction of cytokines occurs, for example excessive production of TNFαor IL-1. It is known that cytokines are produced by a wide variety ofcells such as monocytes and macrophages and that they give rise to avariety of physiological effects which are believed to be important indisease or medical conditions such as inflammation and immunoregulation.For example, and IL-1 have been implicated in the cell signaling cascadewhich is believed to contribute to the pathology of disease states suchas inflammatory and allergic diseases and cytokine-induced toxicity. Itis also known that, in certain cellular systems, TNFα productionprecedes and mediates the production of other cytokines such as IL-1.

Abnormal levels of cytokines have also been implicated in, for example,the production of physiologically-active eicosanoids such as theprostaglandins and leukotrienes, the stimulation of the release ofproteolytic enzymes such as collagenase, the activation of the immunesystem, for example by stimulation of T-helper cells, the activation ofosteoclast activity leading to the resorption of calcium, thestimulation of the release of proteoglycans from, for example,cartilage, the stimulation of cell proliferation and to angiogenesis.

Cytokines are also believed to be implicated in the production anddevelopment of disease states such as inflammatory and allergicdiseases, for example inflammation of the joints (especially rheumatoidarthritis, osteoarthritis and gout), inflammation of thegastrointestinal tract (especially inflammatory bowel disease,ulcerative colitis, Crohn's disease and gastritis), skin disease(especially psoriasis, eczema and dermatitis) and respiratory disease(especially asthma, bronchitis, allergic rhinitis, adult respiratorydistress syndrome and chronic obstructive pulmonary disease), and in theproduction and development of various cardiovascular and cerebrovasculardisorders such as congestive heart failure, myocardial infarction, theformation of atherosclerotic plaques, hypertension, plateletaggregation, angina, stroke. Alzheimer's disease, reperfusion injury,vascular injury including restenosis and peripheral vascular disease,and, for example, various disorders of bone metabolism such asosteoporosis (including senile and postmenopausal osteoporosis), Paget'sdisease, bone metastases, hypercalcaemia, hyperparathyroidism,osteosclerosis, osteoporosis and periodontitis, and the abnormal changesin bone metabolism which may accompany rheumatoid arthritis andosteoarthritis. Excessive cytokine production has also been implicatedin mediating certain complications of bacterial, fungal and/or viralinfections such as endotoxic shock, septic shock and toxic shocksyndrome and in mediating certain complications of CNS surgery or injurysuch as neurotrauma and ischaemic stroke. Excessive cytokine productionhas also been implicated in mediating or exacerbating the development ofdiseases involving cartilage or muscle resorption, pulmonary fibrosis,cirrhosis, renal fibrosis, the cachexia found in certain chronicdiseases such as malignant disease and acquired immune deficiencysyndrome (AIDS), tumour invasiveness and tumour metastasis and multiplesclerosis.

Evidence of the central role played by TNFα in the cell signallingcascade which gives rise to rheumatoid arthritis is provided by theefficacy in clinical studies of antibodies of TNFα (The Lancet, 1994,344, 1125 and British Journal of Rheumatology, 1995, 34, 334).

Thus cytokines such as TNFα and IL-1 are believed to be importantmediators of a considerable range of diseases and medical conditions.Accordingly it is expected that inhibition of the production of and/oreffects of these cytokines will be of benefit in the prophylaxis,control or treatment of such diseases and medical conditions.

Without wishing to imply that the compounds disclosed in the presentinvention possess pharmacological activity only by virtue of an effecton a single biological process, it is believed that the compoundsinhibit the effects of cytokines by virtue of inhibition of the enzymep38 kinase. p38 kinase, otherwise known as cytokine suppressive bindingprotein (hereinafter CSBP) and reactivating kinase(hereinafter RK), is amember of the mitogen-activated protein (hereinafter MAP) kinase familyof enzymes which is known to be activated by physiological stress suchas that induced by ionising radiation, cytotoxic agents, and toxins, forexample endotoxins such as bacterial lipopolysaccharide, and by avariety, of agents such as the cytokines, for example TNFα and IL-1. Itis known that p38 kinase phosphorylates certain intracellular proteinswhich are involved in the cascade of enzymatic steps which leads to thebiosynthesis and excretion of cytokines such as TNFα and IL-1. Knowninhibitors of p38 kinase have been reviewed by G J Hanson in ExpertOpinions on Therapeutic Patents, 1997, 7, 729–733. p38 kinase is knownto exist in isoforms identified as p38α and p38β.

The compounds disclosed in the present invention are inhibitors of theproduction of cytokines such as TNF, in particular of TNFα, and variousinterleukins, in particular IL-1.

Certain 3-(5-benzamido-2-methylphenyl)-3,4-dihydroquinazolin-4-onederivatives were disclosed in Chemical Abstracts, volume 77, abstract19599. The disclosed compounds included:-3-(5-benzamido-2-methylphenyl)-2-methyl-3,4-dihydroquinazolin-4-one,3-[5-(4-methylbenzamido)-2-methylphenyl-2-methyl-3,4-dihydroquinazolin-4-oneand3-[5-(4-methoxybenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-one.

According to one aspect of the present invention there is provided acompound of the

wherein X is —NHCO— or —CONH—; m is 0, 1, 2 or 3; R¹ is hydroxy,halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy,carbamoyl, formyl, (1–6C)alkyl, (2–6C)alkenyl, (2–6C)alkynyl,(1–6C)alkoxy, (1–6C)alkylthio, (1–6C)alkylsulphinyl(1–6C)alkylsulphonyl, (1–6C)alkylamino, di-[(1–6C)alkyl]amino,(1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, (2–6C)alkanoyloxy,(1–6C)alkanoylamino, N-(1–6C)alkyl-(1–6C)alkanoylamino,N-(1–6C)alkylsulphamoyl, N,N-di-[(1–6C)alkyl]sulphamoyl,(1–6C)alkanesulphonylamino, N-(1–6C)alkyl-(1–6C)alkanesulphonylamino,halogeno-(1–6C)alkyl, hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl,cyano-(1–6C)alkyl, amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,di-[(1–6C)alkyl]amino-(1–6C)alkyl, carboxy-(1–6)alkyl,(1–6C)alkoxycarbonyl-(1–6C)alkyl, carbamoyl-(1–6C)alkyl,N-(1–6C)alkylcarbamoyl-(1–6C)alkyl,N,N-di-((1–6C)alkyl]carbamoyl-(1–6C)alkyl, halgeno-(2–6C)alkoxy,hydroxy-(2–6C)alkoxy, (1–6C)alkoxy-(2–6C)alkoxy, cyano-(1–6C)alkoxy,carboxy-(1–6C)alkoxy, alkoxycarbonyl-(1–6C)alkoxy,carbamoyl-(1–6C)alkoxy, N-(1–6C)alkylcarbamoyl-(1–6C)alkoxy,N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkoxy, amino-(2–6C)alkoxy,(1–6C)alkylamino-(2–6C)alkoxy. di-[(1–6C)alkyl]amino-(2–6C)alkoxy,halogeno-(2–6C)alkylamino, hydroxy-(2–6C)alkylamino,(1–6C)alkoxy-(2–6C)alkylamino, cyano-(1–6C)alkylamino,carboxy-(1–6C)alkylamino, (1–6C)alkoxycarbonyl-(1–6C)alkylamino,carbamoyl-(1–6C)alkylamino, N-(1–6C)alkylcarbamoyl-(1–6C)alkylamino,N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkylamino, amino-(2–6C)alkylamino,(1–6C)alkylamino-(2–6C)alkylamino,di-[(1–6C)alkyl]amino-(2–6C)alkyLamino,N-(1–6C)alkyl-halogeno-(1–6C)alkylamino,N-(1–6C)alkyl-hydroxy-(2–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkoxy-(2–6C)alkylamino,N-(1–6C)alkyl-cyano-(1–6C)alkylamino,N-(1–6C)alkyl-carboxy-(1–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkoxycarbonyl-(1–6C )alkylamino,N-(1–6C)alkyl-carbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-N-(1–6C)alkylcarbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-amino-(2–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkylamino-(2–6C)alkylamino,N-(1–6C)alkyl-di-[(1–6C)alkyl]amino-(2–6C)alkylamino,halogeno-(2–6C)alkanoylamino, hydroxy-(2–6C)alkanoylamino,(1–6C)alkoxy-(2–6C)alkanoylamino, cyano-(2–6C)alkanoylamino,carboxy-(2–6C)alkanoylamino, (1–6C)alkoxycarbonyl-(2–6C)alkanoylamino,carbamoyl-(2–6C)alkanoylamino,N-(1–6C)alkylcarbamoyl-(2–6C)alkanoylamino,N,N-di-[(1–6C)alkyl]carbamoyl-(2–6C)alkanoylamino,amino-(2–6C)alkanoylamino, (1–6C)alkylamino-(2–6C)alkanoylamino ordi-[(1–6C)alkyl]amino-(2–6C)alkanoylamino, or R¹ is aryl,aryl-(1–6C)alkyl, aryl-(1–6C)alkoxy, aryloxy, arylamino,N-(1–6C)alkyl-arylamino, aryl-(1–6C)alkylamino,N-(1–6C)alkyl-aryl-(1–6C)alkylamino, aroylamino, arylsulphonylamino,N-arylsulphamoyl, aryl-(2–6C)alkanoylamino, heteroaryl,heteroaryl-(1–6C)alkyl, heteroaryloxy, heteroaryl-(1–6C)alkoxy,heteroarylamino, N-(1–6C)alkyl-heteroarylamino,heteroaryl-(1–6C)alkylamino, N-(1–6C)alkyl-heteroaryl-(1–6C)alkylamino,heteroarylcarbonylamino, heteroarylsulphonylamino,N-heteroarylsulphamoyl, heteroaryl-(2–6C)alkanoylamino,heteroaryl-(1–6C)alkoxy-(1–6C)alkyl, heteroaryl-(1–6C)alkylamino-(1–6C)alkyl,N-(1–6C)alkyl-heteroaryl-(1–6C)alkylamino-(1–6C)alkyl, heterocyclyl,heterocyclyl-(1–6C)alkyl, heterocyclyloxy, heterocyclyl-(1–6C)alkoxy,heterocyclylamino, N-(1–6C)alkyl-heterocyclylamino,heterocyclyl-(1–6C)alkylamino,N-(1–6C)alkyl-heterocyclyl-(1–6C)alkylamino, heterocyclylcarbonylamino,heterocyclylsulphonylamino, N-heterocyclylsulphamoyl,heterocyclyl-(2–6C)alkanoylamino, heterocyclyl-(1–6C)alkoxy-(1–6C)alkyl,heterocyclyl-(1–6C)alkylamino-(1–6C)alkyl orN-(1–6C)alkyl-heterocyclyl-(1–6C)alkylamino-(1–6C)alkyl, or (R¹)m is a(1–6)alkylenedioxy group,and wherein any of the R¹ substituents defined hereinbefore whichcomprises a CH₂ group which is attached to 2 carbon atoms or a CH₂ groupwhich is attached to a carbon atom may optionally bear on each said CH₂,or CH₃ group a substituent selected from hydroxy, amino, (1–6C)alkoxy,(1–6C)alkylamino, di-[(1–6C)alkyl]amino and heterocyclyl, and whereinany aryl, heteroaryl or heterocyclyl group in a R¹ substituent mayoptionally bear 1 or 2 substituents selected from hydroxy, halogeno,(1–6C)alkyl, (1–6C)alkoxy, carboxy, (1–6C)alkoxycarbonyl,N-(1–6C)alkylcarbamoyl, N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl,amino. (1–6C)alkylamino, di-[(1–6C)alkyl]amino, halogeno-(1–6C)alkyl,hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl,amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,di-[(1–6C)alkyl]amino-(1–6C)alkyl, aryl and aryl-(1–6C)alkyl, andwherein any heterocyclyl group in a R¹ substituent may optionally bear 1or 2 oxo or thioxo substituents;n is 0, 1 or 2;R2 is hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino,carboxy, (1–6C)alkoxycarbonyl, (1–6C)alkyl, (2–6C)alkenyl,(2–6C)alkynyl, (1–6C)alkoxy, (1–6C)alkylamino or di-[(1–6C)alkyl]amino;R¹ is hydrogen, halogeno, (1–6C)alkyl or (1–6C)alkoxy;q is 0, 1, 2, 3 or 4; andQ is aryl, aryloxy, aryl-(1–6C)alkoxy, arylamino,N-(1–6C)alkyl-arylamino, aryl-(1–6C)alkylamino,N-(1–6C)alkyl-aryl-(1–6C)alkylamino, aroylamino, arylsulphonylamino,NI-arylcarbamoyl, N-arylsulphamoyl, aryl-(2–6C)alkanoylamino,(3–7C)cycloalkyl. heteroaryl, heteroaryloxy, heteroaryl-(1–6C)alkoxy,heteroarylamino, N-(1–6C)alky heteroarylaminoheteroaryl-(1–6C)alkylamino, N-(1–6C)alkyl-heteroaryl-(1–6C)alkylamino,heteroarylcarbonylamino, heteroarylsulphonylamino.N-heteroarylcarbamoyl, N-heteroarylsulphamoyl,heteroaryl-(2–6C)alkanoylamino, heterocyclyl, heterocyclyloxy,heterocyclyl-(1–6C)alkoxy, heterocyclylamino,N-(1–6C)alkyl-heterocyclylamino, heterocyclyl-(1–6C)alkylamino,N-(1–6C)alkyl-heterocyclyl-(1–6C)alkylamino, heterocyclylcarbonylamino,heterocyclylsulphonylamino, N-heterocyclylcarbamoyl,N-heterocyclylsulphamoyl or heterocyclyl-(2–6C)alkanoylamino, and Q isoptionally substituted with 1, 2 or 3 substituents selected fromhydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino,carboxy, carbamoyl, formyl. (1–6C)alkyl, (2–6C)alkenyl, (2–6C)alkynyl,(1–6C)alkoxy, (1–6C)alkylthio, (1–6C)alkylsulphinyl,(1–6C)alkylsulphonyl, (1–6C)alkylamino, di-[(1–6C)alkyl]amino,(1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, (2–6C)alkanoyloxy,(1–6C)alkanoylamino, N-(1–6C)alkyl-(1–6C)alkanoylamino,N-(1–6C)alkylsulphamoyl, N,N-di-[(1–6C)alkyl]sulphamoyl,(1–6C)alkanesulphonylamino, N-(1–6C)alkyl-(1–6C)alkanesulphonylamino,halogeno-(1–6C)alkyl, hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl,cyano-(1–6C)alkyl, amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,di-[(1–6C)alkyl]amino-(1–6C)alkyl, carboxy-(1–6C)alkyl,(1–6C)alkoxycarbonyl-(1–6C)alkyl, carbamoyl-(1–6C)alkyl,N-(1–6C)alkylcarbamoyl-(1–6C)alkyl,N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkyl, halogeno-(2–6C)alkoxy,hydroxy-(2–6C)alkoxy, (1–6C)alkoxy-(2–6C)alkoxy, cyano-(1–6C)alkoxy,carboxy-(1–6C)alkoxy, (1–6C)alkoxycarbonyl-(1–6C)alkoxy,carbamoyl-(1–6C)alkoxy, N-(1–6C)alkylcarbamoyl-(1–6C)alkoxy,N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkoxy, amino-(2–6C)alkoxy,(1–6C)alkylamino-(2–6C)alkoxy, di-[(1–6C)alkyl]amino-(2–6C)alkoxy,halogeno-(2–6C)alkylamino, hydroxy-(2–6C)alkylamino,(1–6C)alkoxy-(2–6C)alky)amino, cyano-(1–6C)alkylamino,carboxy-(1–6C)alkylamino, (1–6C)alkoxycarbonyl-(1–6C)alkylamino,carbamoyl-(1–6C)alkylamino, N-(1–6C)alkylcarbamoyl-(1–6C)alkylamino,N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkylamino, amino-(2–6C)alkylamino,(1–6C)alkylamino-(2–6C)alkylamino,di-[(1–6C)alkyl]amino-(2–6C)alkylamino,N-(1–6C)alkyl-halogeno-(1–6C)alkylamino,N-(1–6C)alkyl-hydroxy-(2–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkoxy-(2–6C)alkylamino,N-(1–6C)alkyl-cyano-(1–6C)alkylamino, N-(1–6C)alkyl-carboxy-(i-6C)alkylamino, N-(1–6C)alkyl-(1–6C)alkoxycarbonyl-(1–6C)alkylamino,N-(1–6C)alkyl-carbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-N-(1–6C)alkylcarbamoyl-(1–6C)alkylamino,N-(1–6)alkyl-N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-amino-(2–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkylamino-(2–6C)alkylamino,N-(1–6C)alkyl-di-[(1–6C)alkyl]amino-(2–6C)alkylamino,halogeno-(2–6C)alkanoylamino, hydroxy-(2–6C)alkanoylamino,(1–6C)alkoxy-(2–6C)alkanoylamino, cyano-(2–6C)alkanoylamino,carboxy-(2–6C)alkanoylamino, (1–6C)alkoxycarbonyl-(2–6C)alkanoylamino,carbamoyl-(2–6C)alkanoylamino,N-(1–6C)alkylcarbamoyl-(2–6C)alkanoylamino,N,N-di-[(1–6C)alkyl]carbamoyl-(2–6C)alkanoylamino,amino-(2–6C)alkanoylamino, (1–6C)alkylamino-(2–6C)alkanoylamino,di-[(1–6C)alkyl]amino-(2–6C)alkanoylamino, aryl. aryl-(1–6C)alkyl,aryl-(1-6C)alkoxy, aryloxy, arylamino, N-(1–6C)alkyl-arylamino,aryl-(1–6C)alkylamino, N-(1–6C)alkyl-aryl-(1–6C)alkylamino, aroylamino,arylsulphonylamino, N-arylsulphamoyl, aryl-(2–6C)alkanoylamino,heteroaryl, heteroaryl-(1–6C)alkyl, heteroaryloxy,heteroaryl-(1–6C)alkoxy, heteroarylamino, N-(1–6C)alkyl-heteroarylamino,heteroaryl-(1–6C)alkylamino, N-(1–6C)alkyl-heteroaryl-(1–6C)alkylamino,heteroarylcarbonylamino, heteroarylsulphonylamino,N-heteroarylsulphamoyl, heteroaryl-(2–6C)alkanoylamino,heteroaryl-(1–6C)alkoxy-(1–6C)alkyl,heteroaryl-(1–6C)alkylamino-(1–6C)alkyl,N-(1–6C)alkyl-heteroaryl-(1–6C)alkylamino-(1–6C)alkyl, heterocyclyl,heterocyclyl-(1–6C)alkyl, heterocyclyloxy, heterocyclyl-(1–6C)alkoxy,heterocyclylamino, N-(1–6C)alkyl-heterocyclylamino,heterocyclyl-(1–6C)alkylamino,N-(1–6C)alkyl-heterocyclyl-(1–6C)alkylamino, heterocyclylcarbonylamino,heterocyclylsulphonylamino, N-heterocyclylsulphamoyl,heterocyclyl-(2–6C)alkanoylamino, heterocyclyl-(1–6C)alkoxy-(1–6C)alkyl,heterocyclyl-(1–6C)alkylamino, N-6C)alkyl andN-(1–6C)alkyl-heterocyclyl-(1–6C)alkylamino-(1–6C)alkyl,or Q is substituted with a (1–3C)alkylenedioxy group,and wherein any of the substituents on Q defined hereinbefore whichcomprises a CH₂ group which is attached to 2 carbon atoms or a CH₃ groupwhich is attached to a carbon atom may optionally bear on each said CH₂or CH₂ group a substituent selected from hydroxy, amino, (1–6C)alkoxy,(1–6C)alkylamino, di-[(1–6C)alkyl]amino and heterocyclyl, and whereinany aryl, heteroaryl or heterocyclyl group in a bear 1 or 2 substituent;selected from hydroxy, halogeno, (1–6C)alkyl, (1–6C)alkoxy, carboxy,(1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, amine, (1–6C)alkylamino,di-[(1–6C)alkyl]amino, halogeno-(1–6C)alkyl, hydroxy-(1–6C)alkyl,(1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl, amino-(1–6C)alkyl,(1–6C)alkylamino-(1–6C)alkyl, di-((1–6C)alkylamino-(1–6C)alkyl, aryl andaryl-(1–6C)alkyl, and wherein Q when it is a heterocyclyl group or itcontains a heterocyclyl group or any heterocyclyl group in a substituenton Q may optionally bear 1 or 2 oxo or thioxo substituents;or a pharmaceutically-acceptable salt or in-vivo-cleavable esterthereof;except that3-(5-benzamido-2-methylphenyl)-2-methyl-3,4-dihydroquinazolin-4-one,3-[5-(4-methylbenzamido)-2-methylphenyl-2-methyl-3,4-dihydroquinazolin-4-oneand3-[5-(4-methoxybenzamido)-2-methylphenyl-2-methyl-3,4-dihydroquinazolin-4-oneare excluded.

According to a further aspect of the present invention there is provideda compound of

wherein m is 0, 1, 2 or 3;R¹ is hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino,carboxy, carbamoyl, formyl, (1–6C)alkyl, (2–6C)alkenyl, (2–6C)alkynyl,(1–6C)alkoxy, (1–6C)alkylthio, (1–6C)alkylsulphinyl,(1–6C)alkylsulphonyl, (1–6C)alkylamino, di-[(1–6C)alkyl]amino,(1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, (2–6C)alkanoyloxy,(1–6C)alkanoylamino, N-(1–6C)alkylsulphamoyl,N,N-di-[(1–6C)alkyl]sulphamoyl, (1–6C)alkanesulphonylamino,N-(1–6C)alkyl-(1–6C)alkanesulphonylamino, halogeno-(1–6C)alkyl,hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl, amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,di-[(1–6C)alkyl]amino-(1–6C)alkyl, carboxy-(1–6C)alkyl,(1–6C)alkoxycarbonyl-(1–6C)alkyl, carbamoyl-(1–6C)alkyl,N-(1–6C)alkylcarbamoyl-(1–6C)alkyl,N,N-di-[(1–6C)alkyl]carbamoyl-(l-6C)alkyl, halogeno-(2–6C)alkoxy,hydroxy-(2–6)alkoxy. 1–6C )alkoxy-(2–6C)alkoxy, cyano-(1–6C)alkoxy,carboxy-(1–6C)alkoxy,(1–6C)alkoxycarbonyl-(1–6C)alkoxy-carbamoyl-(1–6C)alkoxy,N-(1–6C)alkylcarbamoyl-(1–6C)alkoxy,N,N-di-1-(1–6C)alkyl]carbamoyl-(1–6C)alkoxy, amino-(2–6C)alkoxy,(1–6C)alkylamino-(2–6C)alkoxy, di-[(1–6C)alkyl]amino-(2–6C)alkoxy,halogeno-(2–6C)alkylamino, hydroxy-(2–6C)alkylamino,(1–6C)alkoxy-(2–6C)alkylamino, cyano-(1–6C)alkylamino,carboxy-(1–6C)alkylamino, (1–6C)alkoxycarbonyl-(1–6C)alkylamino,carbamoyl-(1–6C)alkylamino, N-(1–6C)alkylcarbamoyl-(1–6C)alkylamino,N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkylamino, amino-(2–6C)alkylamino,(1–6C)alkylamino-(2–6C)alkylamino,di-[(1–6C)alkyl]amino-(2–6C)alkylamino,N-(1–6C)alkyl-halogeno-(1–6C)alkylamino,N-(1–6C)alkyl-hydroxy-(2–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkoxy-(2–6C)alkylamino,N-(1–6C)alkyl-cyano-(1–6C)alkylamino,N-(1–6C)alkyl-carboxy-(1–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkoxycarbonyl-(1–6C)alkylamino,N-(1–6C)alkyl-carbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-N-(1–6C)alkylcarbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-amino-(2–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkylamino-(2–6C)alkylamino,N-(1–6C)alkyl-di-[(1–6C)alkyl]amino-(2–6C)alkylamino,halogeno-(2–6C)alkanoylamino, hydroxy-(2–6C)alkanoylamino,(1–6C)alkoxy-(2–6C)alkanoylamino, cyano-(2–6C)alkanoylamino,carboxy-(2–6C)alkanoylamino, (1–6C)alkoxycarbonyl-(2–6C)alkanoylamino,carbamoyl-(2–6C)alkanoylamino,N-(1–6C)alkylcarbamoyl-(2–6C)alkanoylamino,N,N-di-[(1–6C)alkyl]carbamoyl-(2–6C)alkanoylamino,;amino-(2–6C)alkanoylamino, (1–6C)alkylamino-(2–6C)alkanoylaminoor di-[(1–6C)alkyl]amino-(2–6C)alkanoylamino,or R¹ is aryl, aryl-(1–6(:)alkyl, aryl-(1–6C)alkoxy, aryloxy, arylamino,N-(1–6C)alkyl-arylamino, aryl-(1–6C)alkylamino,N-(1–6C)alkyl-aryl-(1–6C)alkylamino, aroylamino, arylsulphonylamino,N-arylsulphamoyl, aryl-(2–6C)alkanoylamino, heteroaryl,heteroaryl-(1–6C)alkyl, heteroaryloxy, heteroaryl-(1–6C)alkoxy,heteroarylamino, N-(1–6C)alkyl-heteroarylamino,heteroaryl-(1–6))alkylamino, N-(1–6C)alkyl-heteroaryl-(1–6C)alkylamino,heteroarylcarbonylamino, heteroarylsulphonylamino,N-heteroarylsulphamoyl, heteroaryl-(2–6C)alkanoylamino,heteroaryl-(1–6C)alkoxy-(1–6C)alkyl,heteroaryl-(1–6C)alkylamino-(1–6C)alkyl,N-(1–6C)alkyl-heteroaryl-(1–6C)alkylamino-(1–6C)alkyl, heterocyclyl,heterocyclyl-(1–6C)alkyl, heterocyclyloxy, heterocyclyl-(1–6C)alkoxy,heterocyclylamino, N-(1–6C)alkyl-heterocyclylamino,heterocyclyl-(1–6C)alkylamino,N-(1–6C)alkyl-heterocyclyl-(1–6C)alkylamino, heterocyclylcarbonylamino,heterocyclylsulphonylamino, N-heterocyclylsulphamoyl,heterocyclyl-(2–6C)alkanoylamino, heterocyclyl-(1–6C)alkoxy-(1–6C)alkyl,heterocyclyl-(1–6C)alkylamino-(1–6C)alkyl or N-()-6C)alkyl-heterocyclyl-(1–6C)alkylamino-(1–6C)alkyl,or R2 is a (1–3C)alkylenedioxy group,and wherein any of the R¹ substituents defined hereinbefore whichcomprises a CH, group which is attached to 2 carbon atoms or a CH, groupwhich is attached to a carbon atom may optionally bear on each said CH₂or CH₃ group a substituent selected from hydroxy, amino, (1–6C)alkoxy,(1–6C)alkylamino, di-[(1–6C)alkyl)amino and heterocyclyl, and whereinany aryl, heteroaryl or heterocyclyl group in a R¹ substituent mayoptionally bear 1 or 2 substituents selected from hydroxy, halogeno,(1–6C)alkyl, (1–6C)alkoxy, carboxy, (1–6C)alkoxycarbonyl,N-(1–6C)alkylcarbamoyl, N,N-di-[(1–6C)alkyl)carbamoyl, (2–6C)alkanoyl,amino, (1–6C)alkylamino, di-[(1–6C)alkyl)amino, halogeno-(1–6C)alkyl,hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl,amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,di-[(1–6C)alkyl)amino-(1–6C)alkyl, aryl and aryl-(1–6C)alkyl,n is 0, 1 or 2;R² is hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino,carboxy, (1–6C)alkoxycarbonyl, (1–6C)alkyl, (2–6C)alkenyl,(2–6C)alkynyl, (1–6C)alkoxy, (1–6C)alkylamino or di-[(1–6C)alkyl)amino;R¹ is hydrogen, halogeno, (1–6C)alkyl or (1–6C)alkoxy;q is 0, 1, 2, 3 or 4; andQ is aryl, aryloxy, aryl-(1–6C)alkoxy, arylamino,N-(1–6C)alkyl-arylamino, aryl-(1–6C)alkylamino,N-(1–6C)alkyl-aryl-(1–6C)alkylamino, aroylamino, arylsulphonylamino,N-arylcarbamoyl, N-arylsulphamoyl, aryl-(2–6C)alkanoylamino,(3–7C)cycloalkyl, heteroaryl, heteroaryloxy, heteroaryl-(1–6C)alkoxy,heteroarylamino, N-(1–6C)alkyl-heteroarylamino, heteroaryl-(1–6C)alkylamino, N-(1–6C)alkyl-heteroaryl-(1–6C)alkylamino,heteroarylcarbonylamino, heteroarylsulphonylamino,N-heteroarylcarbamoyl, N-heteroarylsulphamoyl,heteroaryl-(2–6C)alkanoylamino, heterocyclyl, heterocyclyloxy,heterocyclyl-(1–6C)alkoxy, heterocyclylamino,N-(1–6C)alkyl-heterocyclylamino, heterocyclyl-(1–6C)alkylamino,N-(1–6C)alkyl-heterocyclyl-(1–6C)alkylamino, heterocyclylcarbonylamino,heterocyclylsulphonylamino, N-heterocyclylcarbamoyl,N-heterocyclylsulphamoyl or heterocyclyl-(2–6C)alkanoylamino, and Q isoptionally substituted with 1, 2 or 3 substituents selected fromhydroxy, halogeno, trifluoromethyl, cyano. mercapto, nitro, amino,carboxy, carbamoyl, formyl, (1–6C)alkyl, (2–6C)alkenyl, (2–6C)alkynyl,(1–6C)alkoxy, (1–6C)alkylthio, (1–6C)alkylsulphinyl,(1–6C)alkylsulphonyl, (1–6C)alkylamino, di-[(1–6C)alkyl)amino.(1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, (2–6C)alkanoyloxy,(1–6C)alkanoylamino, N-(1–6C)alkylsulphamoyl,N,N-di-[(1–6C)alkyl)sulphamoyl, (1–6C)alkanesulphonylamino,N-(1–6C)alkyl-(1–6(7)alkanesulphonylamino, halogeno-(1–6C)alkyl,hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl,amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6)alkyl,di-[(1–6C)alkyl]amino-(1–6C)alkyl, carboxy-(1–6C)alkyl,(1–6C)alkoxycarbonyl-(1–6C)alkyl, carbamoyl-(1–6C)alky,N-(1–6C)alkylcarbamoyl-(1–6C)alkyl,N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkyl, halogeno-(2–6C)alkoxy,hydroxy-(2–6C)alkoxy, (1–6C)alkoxy-(2–6C)alkoxy, cyano-(1–6C)alkoxy,carboxy-(1–6C)alkoxy, (1–6C)alkoxycarbonyl-(1–6C)alkoxy,carbamoyl-(1–6C)alkoxy, N-(1–6C)alkylcarbamoyl-(1–6C)alkoxy.N,N-di-((1–6C)alkyl]carbamoyl-(1–6C)alkoxy, amino-(2–6C)alkoxy,(1–6C)alkylamino-(2–6C)alkoxy, di-[(1–6C)alkyl]amino-(2–6C)alkoxy,halogeno-(2–6C)alkylamino, hydroxy-(2–6C)alkylamino,(1–6C)alkoxy-(2–6C)alkylamino, cyano-(1–6C)alkylamino,carboxy-(1–6C)alkylamino, (1–6C)alkoxycarbonyl-(1–6C)alkylamino,carbamoyl-(1–6C)alkylamino, N-(1–6C)alkylcarbamoyl-(1–6C)alkylamino,N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkylamino, amino-(2–6C)alkylamino,(1–6C)alkylamino-(2–6C)alkylamino,di-[(1–6C)alkyl]amino-(2–6C)alkylamino,N-(1–6C)alkyl-halogeno-(1–6C)alkylamino,N-(1–6C)alkyl-hydroxy-(2–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkoxy-(2–6C)alkyl amino,N-(1–6C)alkyl-cyano-(1–6C)alkylamino,N-(1–6C)alkyl-carboxy-(1–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkoxycarbonyl-(1–6C)alkylamino,N-(1–6C)alkyl-carbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-N-(1–6C)alkylcarbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-amino-(2–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkylamino-(2–6C)alkylamino,N-(1–6C)alkyl-di-[(1–6C)alkyl]amino-(2–6C)alkylamino,halogeno-(2–6C)alkanoylamino, hydroxy-(2–6C)alkanoylamino,(1–6C)alkoxy-(2–6C)alkanoylamino,cyano-(2–6C)alkanoylamino-carboxy-(2–6C)alkanoylamino,(1–6C)alkoxycarbonyl-(2–6C)alkanoylamino, carbamoyl-(2–6C)alkanoylamino,N-(1–6)alkylcarbamoyl-(2–6C)alkanoylamino,N,N-di-[(1–6C)alkyl]carbamoyl-(2–6C)alkanoylamino,amino-(2–6C)alkanoylamino, (1–6C)alkylamino-(2–6C)alkanoylamino,di-[(1–6C)alkylamino-(2–6C)alkanoylamino, aryl, aryl-(1–6C)alkyl,aryl-(1–6C)alkoxy, aryloxy, arylamino, N-(1–6C)alkyl-arylamino,aryl-(1–6C)alkylamino, N-(1–6C)alkyl aryl-(1–6C)alkylamino, aroylamino,arylsulphonylamino, N-arylsulphamoyl, aryl-(2–6C)alkanoylamino,heteroaryl, heteroaryl-(1–6C)alkyl, heteroaryloxy,heteroaryl-(1–6C)alkoxy. heteroarylamino, N-(1–6C)alkyl-heteroarylamino,heteroaryl-(1–6C)alkylamino, N-(1–6C)alkyl-heteroaryl-(1–6C)alkylamino,heteroarylcarbonylamino, heteroarylsulphonylamino,N-heteroarylsulphamoyl, heteroaryl-(2–6C)alkylamino,heteroaryl-(1–6C)alkoxy-(1–6C)alkyl,heteroaryl-(1–6C)alkylamino-(1–6C)alkyl,N-(1–6C)alkyl-heteroaryl-(1–6C)alkylamino-(1–6C)alkyl, heterocyclyl,heterocyclyl-(1–6C)alkyl, heterocyclyloxy, heterocyclyl-(1–6C)alkoxy.heterocyclylamino, N-(1–6C)alkyl-heterocyclylamino,heterocyclyl-(1–6C)alkylamino,N-(-1–6C)alkyl-heterocyclyl-(1–6C)alkylamino, heterocyclylcarbonylamino,heterocyclylsulphonylamino, N-heterocyclylsulphamoyl,heterocyclyl-(2–6C)alkanoylamino,heterocyclyl-(1–6C)aryloxy-(1–6C)alkyl,heterocyclyl-(1–6C)alkylamino-(1–6C)alkyl andN-(1–6C)alkyl-heterocyclyl-(1–6C)alkylamino-(1–6C)alkyl,or Q is substituted with a (1–3C)alkylenedioxy group,and wherein any of the substituents on Q defined hereinbefore whichcomprises a CH₂ group which is attached to 2 carbon atoms or a CH³ groupwhich is attached to a carbon atom may optionally bear on each said CH²or CH³ group a substituent selected from hydroxy, amino, (1–6C)alkoxy,(1–6C)alkylamino, di-[(1–6C)alkyl]amino and heterocyclyl, and whereinany aryl, heteroaryl or heterocyclyl group in a substituent on Q mayoptionally bear 1 or 2 substituents selected from hydroxy, halogeno,(1–6C)alkyl, (1–6C;)alkoxy, carboxy, (1–6C)alkoxycarbonyl,N-(1–6C)alkylcarbamoyl, N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl,amino, (1–6C)alkylamino, di-((1–6C)alkyl)amino, halogeno-(1–6C)alkyl,hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl,amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,di-[(1–6C)alkyl]amino-(1–6C)alkyl, aryl and aryl-(1–6C)alkyl; or apharmaceutically-acceptable salt or in-vivo-cleavable ester thereof;except that 3-(

-   -   -benzamido-2-methylphenyl)-2-methyl-3,4-dihydroquinazolin-4-one,        3-(;-(4-methylbenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-one,        and 3-(5-(4-methoxybenzamido)-2-methylphenyl]-2-methyl-3        4-dihydroquinazolin-4-one are excluded.

In this specification, the term (1–6C)alkyl includes straight-chain andbranched-chain alkyl groups such as propyl, isopropyl and tert-butyl,and (3–6C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl. However references to individual alkyl groups such as“propyl” are specific for the straight-chain version only, references toindividual branched-chain alkyl groups such as “isopropyl” are specificfor the branched-chain version only and references to individualcycloalkyl groups such as “cyclopentyl” arc specific for that 5-memberedring only. An analogous convention applies to other generic terms, forexample (1–6C)alkoxy includes methoxy, ethoxy, cyclopropyloxy andcyclopentyloxy, (1–6C)alkylamino, includes methylamino, ethylamino,cyclobutylamino and cyclohexylamino, and di-[(1–6C)alkyl]amino includesdimethylamino, diethylamino, N-cyclobutyl-N-methylamino andN-cyclohexyl-N-ethylamino.

It is to be understood that, insofar as certain of the compounds ofFormula 1 defined above may exist in optically active or racemic formsby virtue of one or more asymmetric carbon atoms, the invention includesin its definition any such optically active or racemic form whichpossesses the property of inhibiting cytokines, in particular TNF. Thesynthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis from optically active starting materials or by resolution of aracemic form. Similarly, inhibitory properties against TNF may beevaluated using the standard laboratory techniques referred tohereinafter.

Suitable values for the generic radicals referred to above include thoseset out below.

A suitable value for R¹ or Q when it is aryl, for a substituent on Qwhen it is aryl or for the aryl group within a R¹ substituent or a Qgroup or within a substituent on Q is, for example, phenyl, indenyl,indanyl, naphthyl, tetrahydronaphthyl or fluorenyl, preferably phenyl.

A suitable value for R¹ or Q when it is heteroaryl, for the heteroarylgroup within a R¹ substituent or a Q group, for a substituent on Q whenit is heteroaryl or for the heteroaryl group within a substituent on Qis, for example, an aromatic 5- or 6-membered monocyclic ring, a 9- or10-membered bicyclic ring or a 13- or 14-membered tricyclic ring eachwith up to five ring heteroatoms selected from oxygen, nitrogen andsulphur, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl. oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl,benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl,quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl,naphthyridinyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl,S,S-dioxodibenzothiophenyl, xanthenyl, dibenzo-1,4-diozinyl,phenoxathiinyl, phenoxazinyl, dibenzothfnyl, phenothiazinyl.thianthrenyl, benzofuropyridyl, pyridoindolyl. acridinyl orphenanthridinyl. preferably furyl, thienyl, oxazolyl, isoxazolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl,benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl,quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, naphthyridinyl,carbazolyl, dibenzofuranyl, dibenzothiophenyl or xanthenyl, morepreferably furyl, thienyl, isoxazolyl, thiazolyl, pyridyl, benzothienyl,benzofurazanyl, quinolyl, carbazolyl, dibenzofuranyl ordibenzothiophenyl.

A suitable value for R¹ or Q when it is heterocyclyl, for a substituenton Q when it is heterocyclyl or for the heterocyclyl group within a R¹substituent or a Q group or within a substituent on Q is, for example, anon-aromatic saturated or partially saturated 3- to 10-memberedmonocyclic or bicyclic ring with up to five heteroatoms selected fromoxygen, nitrogen and sulphur, for example oxiranyl, oxetanyl,azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinyl,pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl,1,1-dioxidoisothiazolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl,1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl,piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl,dihydropyrimidinyl or tetrahydropyrimidinyl or benzo derivatives thereofsuch as 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indolinyl,isoindolinyl, chromanyl and isochromanyl, preferably azetidin-1-yl,3-pyrrolin-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,1,1-dioxidoisothiazolidin-2-yl, morpholino,1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidin-3-yl, piperidin-4-yl,homopiperidin-1-yl, piperidino, piperazin-1-yl or homopiperazin-1-yl. Asuitable value for such a group which bears 1 or 2 oxo or thioxosubstituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl,2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl,2,5-dioxopyrrohdinyl, 2.5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.

A suitable value for Q when it is (3–7C)cycloalkyl is, for example, anon-aromatic mono- or bicyciclic 3- to 7-membered carbon ring such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orbicyciclo [2.2,1]heptyl, preferably cyclobutyl cyclopentyl, cyclohexylor cycloheptyl, more preferably cyclohexyl.

Suitable values for various R¹, R¹ or R³ groups, or for varioussubstituents on Q or on an aryl, heteroaryl or heterocyclyl group withinR2 or on an aryl, heteroaryl or heterocyclyl group on a substituent on Qinclude.

for halogeno: fluoro, chloro, bromo and iodo; for (1–6C)alkyl: methyl,ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclopentyl andcyclohexyl; for (2–6C)alkenyl: vinyl and allyl; for (2–6C)alkynyl:ethynyl and 2-propynyl; for (1–6C)alkoxy: methoxy, ethoxy, propoxy,isopropoxy, cyclopropyloxy, butoxy, cyclobutyloxy and cyclopentyloxy;for (1–6C)alkylamino: methylamino, ethylamino, propylamino,cyclobutylamino and cyclohexylamino; for di-[(1–6C)alkyl]amino:dimethylamino, diethylamino and N-ethyl- N-methylamino; for(1–6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyland tert-butoxycarbonyl; for N-(1–6C)alkylcarbamoyl: N-methylcarbamoyl,N-ethylcarbamoyl and N-propylcarbamoyl; forN,N-di-[(1–6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl,N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl; for (2–6C)alkanoyl:acetyl and propionyl; for halogeno-(1–6C)alkyl: fluoromethyl,chloromethyl, bromomethyl, difluoromethyl, dichloromethyl,dibromomethyl, 2-fluoroethyl, 2-chloroethyl and 2-bromoethyl; forhydroxy-(1–6C)alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and3-hydroxypropyl; for (1–6C)alkoxy-(1–6C)alkyl: methoxymethyl,ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and3-methoxypropyl; for cyano-(1–6C)alkyl: cyanomethyl, 2-cyanoethyl,1-cyanoethyl and 3-cyanopropyl; for amino-(1–6C)alkyl: aminomethyl,2-aminoethyl, 1-aminoethyl and 3-aminopropyl; for(1–6C)alkylamino-(1–6C)alkyl: methylaminomethyl, ethylaminomethyl,1-methylaminoethyl, 2-methylaminoethyl, 2-ethylaminoethyl and3-methylaminopropyl; for di-[(1–6C)alkyl]amino-(1–6C)alkyl:dimethylaminomethyl, diethylaminomethyl, 1-dimethylaminoethyl,2-dimethylaminoethyl and 3-dimethylaminopropyl. Suitable values for R¹or Q and suitable values for a substituent on R¹ or Q include:- foraryl-(1–6C)alkyl: benzyl, 2-phenylethyl, 2-phenylpropyl and3-phenylpropyl; for aryl-(1–6C)alkoxy: benzyloxy and 2-phenylethoxy; foraryloxy: phenoxy and 2-naphthyloxy; for arylamino: anilino; forN-(1–6C)alkyl-arylamino: N-methylanilino and N-ethylanilino; foraryl-(1–6C)alkylamino: benzylamino, 2-phenethylamino,2-phenylpropylamino and 3-phenylpropylamino; forN-(1–6C)alkyl-aryl-(1–6C)alkylamino: N-benzyl-N-methylamino; foraroylamino: benzamido and 2-naphthoylamino; arylsulphonylamino:benzenesulphonylamido; for N-arylcarbamoyl: N-phenylcarbamoyl; forN-arylsulphamoyl: N-phenylsulphamoyl; for aryl-(2–6C)alkanoylamino:phenylacetamido and 3-phenylpropionamido; for heteroaryl-(1–6C)alkyl:heteroarylmethyl, 2-heteroarylethyl, 2-heteroarylpropyl and3-heteroarylpropyl; for heteroaryl-(1–6C)alkoxy: heteroarylmethoxy and2-heteroarylethoxy; for N-(1–6C)alkyl-heteroarylamino:N-methylheteroarylamino; for heteroaryl-(1–6C)alkylamino:heteroarylmethylamino, 2-heteroarylethylamino and3-heteroarylpropylamino; for N-(1–6C)alkyl-heteroaryl-(1–6C)alkylamino:N-methylheteroarylmethylamino and N-methyl-2-heteroarylethylamino; forheteroaryl-(2–6C)alkanoylamino: heteroarylacetamido and3-heteroarylpropionamido; for heteroaryl-(1–6C)alkoxy-(1–6C)alkyl:heteroarylmethoxymethyl, 2-heteroarylethoxymethyl and3-heteroarylpropoxymethyl; for heteroaryl-(1–6C)alkylamino-(1–6C)alkyl:heteroarylmethylaminomethyl, 2-heteroarylethylaminomethyl and3-heteroarylpropylaminomethyl; forN-(1–6C)alkyl-heteroaryl-(1–6C)alkylamino-(1–6C)alkyl:N-heteroarylmethyl- N-methylaminomethyl, N-(2-heteroarylethyl)-N-methylaminomethyl and N-(3-heteroarylpropyl)- N-methylaminomethyl; forheterocyclyl-(1–6C)alkyl: heterocyclylmethyl, 2-heterocyclylethyl,2-heterocyclylpropyl and 3-heterocyclylpropyl; forheterocyclyl-(1–6C)alkoxy: heterocyclylmethoxy and 2-heterocyclylethoxy;for N-(1–6C)alkyl-heterocyclylamino: N-methylheterocyclylamino; forheterocyclyl-(1–6C)alkylamino: heterocyclylmethylamino,2-heterocyclylethylamino and 3-heterocyclylpropylamino; forN-(1–6C)alkyl-heterocyclyl-(1–6C)alkylamino:N-methylheterocyclylmethylamino and N-methyl-2-heterocyclylethylamino;for heterocyclyl-(2–6C)alkanoylamino: heterocyclylacetamido and3-heterocyclylpropionamido; for heterocyclyl-(1–6C)alkoxy-(1–6C)alkyl:heterocyclylmethoxymethyl, 2-heterocyclylethoxymethyl and3-heterocyclylpropoxymethyl; forheterocyclyl-(1–6C)alkylamino-(1–6C)alkyl:heterocyclylmethylaminomethyl, 2-heterocyclylethylaminomethyl and3-heterocyclylethylaminomethyl; forN-(1–6C)alkyl-heterocyclyl-(1–6C)alkylamino-(1–6C)alkyl:N-heterocyclylmethyl- N-methylaminomethyl, N-(2-heterocyclylethyl)-N-methylaminomethyl and N-(3-heterocyclylpropyl)- N-methylaminomethyl;for (1–3C)alkylenedioxy: methylenedioxy, ethylenedioxy andtrimethylenedioxy; for (1–6C)alkylthio: methylthio, ethylthio andpropylthio; for (1–6C)alkylsulphinyl: methylsulphinyl, ethylsulphinyland propylsulphinyl; for (1–6C)alkylsulphonyl: methylsulphonyl,ethylsulphonyl and propylsulphonyl; for (2–6C)alkanoyloxy: acetoxy andpropionyloxy: for (1–6C)alkanoylamino: formamido, acetamido andpropionamido; for N-(1–6C)alkyl-(1–6C)alkanoylamino: N-methylacetamidoand N-methylpropionamido; for N-(1–6C)alkylsulphamoyl:N-methylsulphamoyl and N-ethylsulphamoyl; forN,N-di-[(1–6C)alkyl]sulphamoyl: N,N-dimethylsulphamoyl; for(1–6C)alkanesulphonylamino: methanesulphonamido and ethanesulphonamido;for N-(1–6C)alkyl-(1–6C)alkanesulphonylamino:N-methylmethanesulphonylamino and N-methylethanesulphonylamino; forcarboxy-(1–6C)alkyl: carboxymethyl, 1-carboxyethyl, 2-carboxyethyl,3-carboxypropyl and 4-carboxybutyl; for(1–6C)alkoxycarbonyl-(1–6C)alkyl: methoxycarbonylmethyl,ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, 1-methoxycarbonylethyl,1-ethoxycarbonylethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl,3-methoxycarbonylpropyl and 3-ethoxycarbonylpropyl; forcarbamoyl-(1–6C)alkyl: carbamoylmethyl, 1-carbamoylethyl,2-carbamoylethyl and 3-carbamoylpropyl; forN-(1–6C)alkylcarbamoyl-(1–6C)alkyl: N-methylcarbamoylmethyl,N-ethylcarbamoylmethyl, N-propylcarbamoylmethyl,1-(N-methylcarbamoyl)ethyl, 1-(N-ethylcarbamoyl)ethyl,2-(N-methylcarbamoyl)ethyl, 2-(N-ethylcarbamoyl)ethyl and3-(N-methylcarbamoyl)propyl; forN,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkyl: N,N-dimethylcarbamoylmethyl,N-ethyl-N-methylcarbamoylmethyl, N,N-diethylcarbamoylmethyl,1-(N,N-dimethylcarbamoyl)ethyl, 1-(N,N-diethylcarbamoyl)ethyl,2-(N,N-dimethylcarbamoyl)ethyl, 2-(N,N-diethylcarbamoyl)ethyl,3-(N,N-dimethylcarbamoyl)propyl and 4-(N,N-dimethylcarbamoyl)butyl; forhalogeno-(2–6C)alkoxy: 2-chloroethoxy, 2-bromoethoxy, 3-chloropropoxy,1,1,2,2-tetrafluoroethoxy and 2,2,2-trifluoroethoxy; forhydroxy-(2–6C)alkoxy: 2-hydroxyethoxy, 3-hydroxypropoxy, 2-hydroxy-1-methylethoxy, 2-hydroxy-2-propoxy and 4-hydroxybutoxy; for(1–6C)alkoxy-(2–6C)alkoxy: 2-methoxyethoxy, 2-ethoxyethoxy,3-methoxypropoxy, 2-methoxy-1-methylethoxy and 4-ethoxybutoxy; forcyano-(1–6C)alkoxy: cyanomethoxy, 2-cyanoethoxy and 3-cyanopropoxy; forcarboxy-(1–6C)alkoxy: carboxymethoxy, 1-carboxyethoxy, 2-carboxyethoxyand 3-carboxypropoxy; for (1–6C)alkoxycarbonyl-(1–6C)alkoxy:methoxycarbonylmethoxy, ethoxycarbonylmethoxy,tert-butoxycarbonylmethoxy, 2-methoxycarbonylethoxy and3-ethoxycarbonylpropoxy; for carbamoyl-(1–6C)alkoxy: carbamoylmethoxyand 2-carbamoylethoxy; for N-(1–6C)alkylcarbamoyl-(1–6C)alkoxy:N-methylcarbamoylmethoxy, 2-(N-ethylcarbamoyl)ethoxy and3-(N-methylcarbamoyl)propoxy; forN,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkoxy:N,N-dimethylcarbamoylmethoxy, 2-(N,N-dimethylcarbamoyl)ethoxy and3-(N,N-diethylcarbamoyl)propoxy; for amino-(2–6C)alkoxy: 2-aminoethoxy,2-amino-1-methylethoxy, 3-aminopropoxy, 2-amino-2-methylpropoxy and4-aminobutoxy; for (1–6C)alkylamino-(2–6C)alkoxy: 2-methylaminoethoxy,2-methylamino-1-methylethoxy and 3-ethylaminopropoxy; fordi-[(1–6C)alkyl]amino-(2–6C)alkoxy: 2-dimethylaminoethoxy,2-diethylaminoethoxy, 2-dimethylaminopropoxy, 2-dimethylamino-2-methylethoxy, 3-dimethylaminopropoxy and 4-dimethylaminobutoxy; forhalogeno-(2–6C)alkylamino: 2-fluoroethylamino, 2-chloroethylamino,2-bromoethylamino, 3-fluoropropylamino and 3-chloropropylamino; forhydroxy-(2–6C)alkylamino: 2-hydroxyethylamino, 3-hydroxypropylamino,2-hydroxy-2-methylpropylamino and 4-hydroxybutylamino; for(1–6C)alkoxy-(2–6C)alkylamino: 2-methoxyethylamino, 2-ethoxyethylamino,3-methoxypropylamino and 3-ethoxypropylamino; forcyano-(1–6C)alkylamino: cyanomethylamino, 2-cyanoethylamino and3-cyanopropylamino; for carboxy-(1–6C)alkylamino: carboxymethylamino,1-carboxyethylamino, 2-carboxyethylamino and 3-carboxypropylamino; for(1–6C)alkoxycarbonyl-(1–6C)alkylamino: methoxycarbonylmethylamino,2-(ethoxycarbonyl)ethylamino and 3-(tert-butoxycarbonyl)propylamino; forcarbamoyl-(1–6C)alkylamino: carbamoylmethylamino and2-carbamoylethylamino; for N-(1–6C)alkylcarbamoyl-(1–6C)alkylamino:N-methylcarbamoylmethylamino, N-ethylcarbamoylmethylamino and2-(N-methylcarbamoyl)ethylamino; forN,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkylamino:N,N-dimethylcarbamoylmethylamino, N,N-diethylcarbamoylmethylamino and2-(N,N-dimethylcarbamoyl)ethylamino; for amino-(2–6C)alkylamino:2-aminoethylamino, 3-aminopropylamino, 2-amino-2-methylpropylamino and4-aminobutylamino; for (1–6C)alkylamino-(2–6C)alkylamino:2-methylaminoethylamino, 2-ethylaminoethylamino,2-propylaminoethylamino, 3-methylaminopropylamino,3-ethylaminopropylamino, 2-methylamino-2-methylpropylamino and4-methylaminobutylamino; for di-[(1–6C)alkyl]amino-(2–6C)alkylamino:2-dimethylaminoethylamino, 2-(N-ethyl-N-methylamino)ethylamino,2-diethylaminoethylamino, 2-dipropylaminoethylamino,3-dimethylaminopropylamino, 3-diethylaminopropylamino,2-dimethylamino-2-methylpropylamino and 4-dimethylaminobutylamino; forN-(1–6C)alkyl-halogeno-(2–6C)alkylamino:N-(2-chloroethyl)-N-methylamino, N-(2-bromoethyl)-N-methylamino andN-(2-bromoethyl)-N-ethylamino; forN-(1–6C)alkyl-hydroxy-(2–6C)-alkylamino:N-(2-hydroxyethyl)-N-methylamino, N-(3-hydroxypropyl)-N-methylamino andN-ethyl-N-(2-hydroxyethyl)amino; forN-(1–6C)alkyl-(1–6C)alkoxy-(2–6C)alkylamino:N-methyl-N-(2-methoxyethyl)amino, N-methyl-N-(3-methoxypropyl)amino andN-ethyl-N-(2-methoxyethyl)amino; forN-(1–6C)alkyl-cyano-(1–6C)alkylamino: N-(cyanomethyl)-N-methylamino; forN-(1–6C)alkyl-carboxy-(1–6C)alkylamino: N-carboxymethyl-N-methylaminoand N-(2-carboxyethyl)-N-methylamino; forN-(1–6C)alkyl-(1–6C)alkoxycarbonyl-(1–6C)alkylamino:N-methoxycarbonylmethyl-N-methylamino,N-(2-ethoxycarbonylethyl)-N-ethylamino andN-(2-tert-butoxycarbonylethyl)-N-methylamino; forN-(1–6C)alkyl-carbamoyl-(1–6C)alkylamino:N-carbamoylmethyl-N-methylamino and N-(2-carbamoylethyl)-N-methylamino;for N-(1–6C)alkyl-N-(1–6C)alkylcarbamoyl-(1–6C)alkylamino:N-(N-methylcarbamoylmethyl)-N-methylamino,N-(N-ethylcarbamoylmethyl)-N-methylamino andN-[2-(N-methylcarbamoyl)ethyl]-N-methylamino; forN-(1–6C)alkyl-N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkylamino:N-(N,N-dimethylcarbamoylmethyl)-N-methylamino andN-[2-(N,N-dimethylcarbamoyl)ethyl]-N-methylamino; forN-(1–6C)alkyl-amino-(2–6C)alkylamino: N-(2-aminoethyl)-N-methylamino,N-(3-aminopropyl)-N-methylamino and N-(4-aminobutyl)-N-methylamino; forN-(1–6C)alkyl-(1–6C)alkylamino-(2–6C)alkylamino: N-(2-methylaminoethyl)-N-methylamino, N-(2-methylaminoethyl)- N-methylamino,N-(3-methylaminopropyl)- N-methylamino,N-(3-ethylaminopropyl)-N-ethylamino andN-(4-methylaminobutyl)-N-methylamino; forN-(1–6C)alkyl-di-[(1–6C)alkyl]amino-(2–6C)alkylamino:N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino andN-(4-dimethylaminobutyl)-N-methylamino; forhalogeno-(2–6C)alkanoylamino: 2-chloroacetamido and3-chloropropionamido; for hydroxy-(2–6C)alkanoylamino:2-hydroxyacetamido and 3-hydroxypropionamido; for(1–6C)alkoxy-(2–6C)alkanoylamino: 2-methoxyacetamido and3-methoxypropionamido; for cyano-(2–6C)alkanoylamino: 2-cyanoacetamidoand 3-cyanopropionamido; for carboxy-(2–6C)alkanoylamino:2-carboxyacetamido and 3-carboxypropionamido; for(1–6C)alkoxycarbonyl-(2–6C)alkanoylamino: 2-methoxycarbonylacetamido,2-(tert-butoxycarbonyl)acetamido and 3-methoxycarbonylpropionamido; forcarbamoyl-(2–6C)alkanoylamino: 2-carbamoylacetamido,3-carbamoylpropionamido and 4-carbamoylbutyramido; forN-(1–6C)alkylcarbamoyl-(2–6C)alkanoylamino:2-(N-methylcarbamoyl)acetamido and 3-(N-ethylcarbamoyl)propionamido; forN,N-di-[(1–6C)alkyl]carbamoyl-(2–6C)alkanoylamino:2-(N,N-dimethylcarbamoyl)acetamido, 2-(N,N-diethylcarbamoyl)acetamidoand 3-(N,N-dimethylcarbamoyl)propionamido; foramino-(2–6C)alkanoylamino: 2-aminoacetamido, 2-aminopropionamido and3-aminopropionamido; for (1–6C)alkylamino-(2–6C)alkanoylamino:2-methylaminoacetamido, 2-ethylaminoacetamido, 2-methylaminopropionamidoand 3-methylaminopropionamido; fordi-[(1–6C)alkyl]amino-(2–6C)alkanoylamino: 2-dimethylaminoacetamido,2-diethylaminoacetamido, 2-dimethylaminopropionamido and3-dimethylaminopropionamido.

When, as defined hereinbefore, any of the substituents on R¹ or Q whichcomprises a CH₂, group which is attached to 2 carbon atoms or a CH₂group which is attached to a carbon atom may optionally bear on eachsaid CH₂ or CH₃ group a substituent selected from hydroxy, amino,(1–6C)alkoxy, (1–6C)alkylamino, di-[(1–6C)alkyl]amino and heterocyclyl,suitable substituents so formed include, for example, substitutedheterocyclyl-(1–6C)alkoxy groups such as 2-hydroxy-3-piperidinopropoxyand 2-hydroxy-3-morpholinopropoxy, substituted amino-(2–6C)alkoxy groupssuch as 3-amino-2-hydroxypropoxy, substituted(1–6C)alkylamino-(2–6C)alkoxy groups such as2-hydroxy-3-methylaminopropoxy, substituteddi-[(1–6C)alkyl]amino-(2–6C)alkoxy groups such as3-dimethylamino-2-hydroxypropoxy,3-[N-(3-dimethylaminopropyl)-N-methylamino]propoxy and3N-(3-dimethylaminopropyl)-N-methylamino-2-hydroxypropoxy, substitutedheterocyclyl-(1–6C)alkylamino groups such as2-hydroxy-3-piperidinopropylamino and 2-hydroxy-3-morpholinopropylamino,substituted amino-(2–6C)alkylamino groups such as3-amino-2-hydroxypropylamino. substituted(1–6C)alkylamino-(2–6C)alkylamino groups such as2-hydroxy-3-methylaminopropylamino, substituteddi-[(1–6C)alkylamino-(2–6C)alkylamino groups such as3-dimethylamino-2-hydroxypropylamino,3-[N-(3-dimethylaminopropyl)-N-methylamino]propylamino and3-[N-(3-dimethylaminopropyl)-N-ntethylamino]-2-hydroxypropylamino andsubstituted (1–6C)alkylamino-(1–6C)alkyl groups such as2-dimetlrylaminoethylaminomethyl, 3-dimethylaminopropylaminomethyl,3-dimethylamino-2,2-dimethylpropylaminomethyl,2-morpholinoethylaminomethyl, 2-piperazin-1-ylethylaminomethyl and3-morpholinopropylaminomethyl.

A suitable pharmaceutically-acceptable salt of a compound of the FormulaIa or Ib is for example, an acid-addition salt of a compound of theFormula Ia or Ib which is sufficiently basic, for example anacid-addition salt with an inorganic or organic acid such ashydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleicacid; or, for example a salt of a compound of the Formula Ia or Ib whichis sufficiently acidic, for example an alkali or alkaline earth metalsalt such as a calcium or magnesium salt, or an ammonium salt, or a saltwith an organic base such as methylamine, dimethylamino, triethylamine,piperidino, morpholine or tris-(2-hydroxyethyl)amine.

Various forms of prodrugs are known in the art. For examples of suchprodrug derivatives, see:

-   -   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985)        and Methods in Enzymology, Vol. 42, p. 309–396, edited by K.        Widder, et al. (Academic Press, 1985);    -   b) A Textbook of Drug Design and Development, edited by        Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and        Application of Prodrugs”, by H. Bundgaard p 113–191 (1991);    -   c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1–38 (1992);    -   d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77,        285 (1988); and    -   e) N. Kakeya, et al., Chem. Pharm. Bull. 32, 692 (1984).

Examples of such pro-drugs may be used to form in-vivo-cleavable estersof a compound of the Formula Ia or Ib. An in-vivo-cleavable ester of acompound of the Formula Ia or Ib containing a carboxy group is, forexample a pharmaceutically-acceptable ester which is cleaved in thehuman or animal body to produce the parent acid. Suitablepharmaceutically-acceptable esters for carboxy include(1–6C)alkoxymethyl esters, for example methoxymethyl;(1–6C)alkanoyloxymethyl esters, for example pivaloyloxymethyl;phthalidyl esters; (3–8C)cycloalkoxycarbonyloxy(1–6C)alkyl esters, forexample 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-ylmethyl esters,for example 5-methyl-1,3-dioxolan-2-ylmethyl; and(1–6C)alkoxycarbonyloxyethyl esters, for example1-methoxycarbonyloxyethyl; and may be formed at any carboxy group in thecompounds of this invention.

Particular novel compounds of the invention include, for example, amidederivatives of the Formula Ia or Ib as appropriate, orpharmaceutically-acceptable salts thereof, wherein:

-   -   (a) R³ is hydrogen or (1–6C)alkyl such as methyl, ethyl, propyl        and isopropyl, preferably R³ is hydrogen, methyl or ethyl, more        preferably hydrogen or methyl; and X, R¹, R², Q, m, n and q as        appropriate have any of the meanings defined hereinbefore or in        this section relating to particular novel compounds of the        invention.    -   (b) Q is phenyl or a heteroaromatic 5- or 6-membered monocyclic        ring or a 9- or 10-membered bicyclic ring with up to five ring        heteroatoms selected from oxygen, nitrogen and sulphur which        bears a basic substituent selected from the substituents for Q        defined hereinbefore; and X, R¹, R², R³, m, n and q as        appropriate have any of the meanings defined hereinbefore or in        this section relating to particular novel compounds of the        invention;    -   (c) Q is phenyl. indenyl, indanyl or fluorenyl which optionally        bears 1, 2 or 3 substituents selected from the substituents for        Q defined hereinbefore; and X, R¹, R², R³, m, n and q as        appropriate have any of the meanings defined hereinbefore or in        this section relating to particular novel compounds of the        invention;    -   (d) Q is phenyl or a heteroaromatic 5- or 6-membered monocyclic        ring or a 9- or 10membered bicyclic ring with up to five ring        heteroatoms selected from oxygen, nitrogen and sulphur which        bears a basic substituent selected from amino, (1–6C)alkylamino,        di-[(1–6C)alkyl]amino, amino-(1–6C)alkyl,        (1–6C)alkylamino-(1–6C)alkyl, di-[(1–6C)alkyl]amino-(1–6C)alkyl,        amino-(2–6C)alkoxy, (1–6C)alkylamino-(2–6C)alkoxy,        di-[(1–6C)alkyl]amino-(2–6C)alkoxy, amino-(2–6C)alkylamino,        (1–6C)alkylamino-(2–6C)alkylamino,        di-[(1–6C)alkyl]amino-(2–6C)alkylamino,        N-(1–6C)alkyl-amino-(2–6C)alkylamino,        N-(1–6C)alkyl-(1–6C)alkylamino-(2–6C)alkylamino,        N-(1–6C)alkyl-di-[(1–6C)alkyl]amino-(2–6C)alkylamino,        amino-(2–6C)alkanoylamino, (1–6C)alkylamino-(2–6C)alkanoylamino,        di-[(1–6C)alkyl]amino-(2–6C)alkanoylamino, heteroaryl,        heteroaryl(1–6C)alkyl, heteroaryl-(1–6C)alkoxy, heterocyclyl,        heterocyclyl-(1–6C)alkyl and heterocyclyl-(1–6C)alkoxy, and        wherein any heteroaryl or heterocyclyl group in a basic        substituent on Q may optionally bear 1 or 2 substituents        selected from halogeno, (1–6C)alkyl, (2–6C)alkanoyl, amino,        (1–6C)alkylamino and di-[(1–6C)alkyl]amino; and X, R¹, R², R³,        m, n and q as appropriate have any of the meanings defined        hereinbefore or in this section relating to particular novel        compounds of the invention; (e) Q is phenyl or a heteroaromatic        5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic        ring with up to five ring heteroatoms selected from oxygen,        nitrogen and sulphur which optionally bears 1, 2 or 3        substituents selected from hydroxy, halogeno, trifluoromethyl,        cyano, nitro, amino, carboxy, (1–6C)alkyl, (1–6C)alkoxy,        (1–6C)alkylamino, di-[(1–6C)alkyl]amino, (1–6C)alkoxycarbonyl,        (2–6C)alkanoyl, halogeno-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl,        amino-(1–6C)alkyl, (1–6C)alkylamino-( 1–6C)alkyl,        di-[(1–6C)alkyl]amino-(1–6C)alkyl, halogeno-(2–6C)alkoxy,        hydroxy-(2–6C)alkoxy, (1–6C)alkoxy-(2–6C)alkoxy,        cyano-(1–6C)alkoxy, carboxy-(1–6C)alkoxy,        (1–6C)alkoxycarbonyl-(1–6C)alkoxy, amino-(2–6C)alkoxy,        (1–6C)alkylamino-(2–6C)alkoxy,        di-[(1–6C)alkyl]amino-(2–6C)alkoxy, pyridyl, imidazolyl,        pyridyl-(1–6C)alkyl, imidazolyl-(1–6C)alkyl,        pyridyl-(1–6C)alkoxy, imidazolyl-(1–6C)alkoxy, pyrrolidinyl,        piperidinyl, morpholinyl, piperazinyl, 4-(1–6C)alkylpiperazinyl,        4-(2–6C)alkanoylpiperazinyl, pyrrolidinyl-(1–6C)alkyl,        piperidinyl-(1–6C)alkyl, morpholinyl-(1–6C)alkyl,        piperazinyl(1–6C)alkyl, 4-(1–6C)alkylpiperazinyl-(1–6C)alkyl,        4-(2–6C)alkanoylpiperazinyl-(1–6C)alkyl, pyrrolidinyloxy,        piperidinyloxy, 1-(1–6C)alkylpiperidinyloxy,        pyrrolidinyl-(2–6C)alkoxy, piperidinyl-(2–6C)alkoxy,        morpholinyl-(2–6C)alkoxy, piperazinyl-(2–6C)alkoxy,        4-(1–6C)alkylpiperazinyl-(2–6C)alkoxy and        4-(2–6C)alkanoylpiperazinyl-(2–6C)alkoxy or Q bears a        (1–3C)alkylenedioxy substituent; and X, R¹, R², R³, m, n and q        as appropriate have any of the meanings defined hereinbefore or        in this section relating to particular novel compounds of the        invention;    -   (f) Q is phenyl, indenyl, indanyl, fluorenyl or a heteroaromatic        5- or 6-membered monocyclic ring with up to three ring        heteroatoms selected from oxygen, nitrogen and sulphur which        optionally bears 1, 2 or 3 substituents selected from hydroxy,        halogeno, trifluoromethyl, cyano, nitro, amino, carboxy,        (1–6C)alkyl, (1–6C)alkoxy, (1–6C)alkylamino,        di-[(1–6C)alkyl]amino, (1–6C)alkoxycarbonyl, (2–6C)alkanoyl,        (1–6C)alkanoylamino, N-(1–6C)alkyl-(1–6C)alkanoylamino,        (1–6C)alkanesulphonylamino,        N-(1–6C)alkyl-(1–6C)alkanesulphonylamino, phenyl, furyl,        thienyl, azetidinyl, pyrrolinyl, pyrrolidinyl,        1,1-dioxidoisothiazolidinyl, piperidinyl, homopiperidinyl,        morpholinyl, piperazinyl, homopiperazinyl,        pyrrolidinyl-(1–6C)alkyl, piperidinyl-(1–6C)alkyl,        morpholinyl-(1–6C)alkyl and piperazinyl-(1–6C)alkyl, and wherein        any phenyl, furyl thienyl or heterocyclyl group in a substituent        on Q may optionally bear 1 or 2 substituents selected from        halogeno, (1–6C)alkyl, (1–6C)alkoxy and (2–6C)alkanoyl; and X,        R¹, R², R³, m, n and q as appropriate have any of the meanings        defined hereinbefore or in this section relating to particular        novel compounds of the invention;    -   (g) Q is phenyl, furyl, thienyl, oxazolyl, isoxazolyl,        imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl,        pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl,        benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl,        indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl,        quinoxalinyl or naphthyridinyl which optionally bears 1 or 2        substituents selected from those defined in paragraph (b), (d)        or (e) hereinbefore; and X, R¹, R², R³, m, n and q as        appropriate have any of the meanings defined hereinbefore or in        this section relating to particular novel compounds of the        invention;    -   (h) Q is phenyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or        5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-imidazolyl, 3-        or 4-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl,        2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 2-, 4- or        5-pyrimidinyl, 2-pyrazinyl, 2-, 3-, 5- or 6-benzofuranyl, 2-,        3-, 5- or 6-indolyl, 2-, 3-, 5- or 6-benzothienyl, 2-, 5- or        6-benzoxazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 5- or        6-benzothiazolyl, 3-, 5- or 6-indazolyl, 5-benzofurazanyl, 2-,        3-, 6- or 7-quinolyl, 3-, 6- or 7-isoquinolyl, 2-, 6- or        7-quinazolinyl, 2-, 6- or 7-quinoxalinyl, or        1,8-naphthyridin-2-yl or 1,8-naphthyridin-3-yl which optionally        bears 1 or 2 substituents selected from those defined in        paragraph (b), (d) or (e) hereinbefore; and X, R¹, R², R³, m, n        and q as appropriate have any of the meanings defined        hereinbefore or in this section relating to particular novel        compounds of the invention;    -   (i) Q is a heteroaromatic 5- or 6-membered monocyclic ring, a 9-        or 10-membered bicyclic ring or a 13- or 14-membered tricyclic        ring each with up to five ring heteroatoms selected from oxygen,        nitrogen and sulphur which optionally bears 1, 2 or 3        substituents selected from hydroxy, halogeno, trifluoromethyl,        cyano nitro, amino, carboxy, (1–6C)alkyl, (1–6C)alkoxy,        (1–3C)alkylenedioxy, (1–6C)alkylamino, di-[(1–6C)alkyl]amino and        (1–6C)alkoxycarbonyl; and X, R¹, R², R³, m, n and q as        appropriate have any of the meanings defined hereinbefore or in        this section relating to particular novel compounds of the        invention;    -   (j) Q is a heteroaromatic 13- or 14-membered tricyclic ring each        with up to five ring heteroatoms selected from oxygen, nitrogen        and sulphur which optionally bears 1, 2 or 3 substituents        selected from hydroxy, halogeno, trifluoromethyl, cyano, nitro,        amino, carboxy, (1–6C)alkyl, (1–6C)alkoxy, (1–3C)alkylenedioxy,        (1–6C)alkylamino, di-[(1–6C)alkyl]amino and        (1–6C)alkoxycarbonyl; and X, R¹, R², R³, m, n and q as        appropriate have any of the meanings defined hereinbefore or in        this section relating to particular novel compounds of the        invention;    -   (k) Q is furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl,        pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl,        pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiophenyl,        benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl,        benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl,        quinoxalinyl, naphthyridinyl, carbazolyl, dibenzofuranyl,        dibenzothiophenyl or xanthenyl which optionally bears 1 or 2        substituents selected from those defined in paragraph (i)        hereinbefore; and X, R¹, R², R³, m, n and q as appropriate have        any of the meanings defined hereinbefore or in this section        relating to particular novel compounds of the invention;    -   (l) Q is 1-, 2- or 3-carbazolyl, 1-, 2-, 3- or 4-dibenzofuranyl        or 1-, 2-, 3- or 4-dibenzothiophenyl which optionally bears 1 or        2 substituents selected from those defined in paragraph (i)        hereinbefore; and X, R¹, R², R³, m, n and q as appropriate have        any of the meanings defined hereinbefore or in this section        relating to particular novel compounds of the invention;    -   (m) n is 0; and X, R¹, R³, Q, m and q as appropriate have any of        the meanings defined hereinbefore or in this section relating to        particular novel compounds of the invention;    -   (n) n is 1 and R² is halogeno or (1–6C)alkyl: and X, R¹, R³, Q,        m and q as appropriate have any of the meanings defined        hereinbefore or in this section relating to particular novel        compounds of the invention;    -   (o) q is 0,and X, R², R³, Q, m and n as appropriate have any of        the meanings defined hereinbefore or in this section relating to        particular novel compounds of the invention;    -   (p) m is 1 and R¹ is amino, (1–6C)alkylamino,        di-[(1–6C)alkyl]amino, amino-(1–6C)alkyl,        (1–6C)alkylamino-(1–6C)alkyl, di-[(1–6C)alkyl]amino-(1–6C)alkyl,        amino-(2–6C)alkoxy, (1–6C)alkylamino-(2–6C)alkoxy,        di-[(1–6C)alkyl]amino-(2–6C)alkoxy, amino-(2–6C)alkylamino,        (1–6C)alkylamino-(2–6C)alkylamino,        di-[(1–6C)alkyl]amino-(2–6C)alkylamino,        N-(1–6C)alkyl-amino-(2–6C)alkylamino,        N-(1–6C)alkyl-(1–6C)alkylamino-(2–6C)alkylamino,        N-(1–6C)alkyl-di-[(1–6C)alkyl]amino-(2–6C)alkylamino,        heteroaryl, heteroaryl-(1–6C)alkyl, heteroaryl-(1–6C)alkoxy,        heterocyclyl, heterocyclyl-(1–6C)alkyl, heterocyclyloxy or        heterocyclyl-(1–6C)alkoxy, and wherein any heteroaryl or        heterocyclyl group in a R¹ substituent may optionally bear 1 or        2 substituents selected from hydroxy, halogeno, (1–6C)alkyl,        (1–6C)alkoxy, (2–6C)alkanoyl, amino, (1–6C)alkylamino and        di-[(1–6C)alkyl]amino; and X, R², R³, Q, n and q as appropriate        have any of the meanings defined hereinbefore or in this section        relating to particular novel compounds of the invention;    -   (q) m is 1 and R¹ is amino, (1–6C)alkylamino,        di-[(1–6C)alkyl]amino, amino-(1–6C)alkyl,        (1–6C)alkylamino-(1–6C)alkyl, di-[(1–6C)alkyl]amino-(1–6C)alkyl,        amino-(2–6C)alkoxy, (1–6C)alkylamino-(2–6C)alkoxy,        di-[(1–6C)alkyl]amino-(2–6C)alkoxy, amino-(2–6C)alkylamino,        (1–6C)alkylamino-(2–6C)alkylamino,        di-[(1–6C)alkyl]amino-(2–6C)alkylamino,        N-(1–6C)alkyl-amino-(2–6C)alkylamino,        N-(1–6C)alkyl-(1–6C)alkylamino-(2–6C)alkylamino,        N-(1–6C)alkyl-di-[(1–6C)alkyl]amino-(2–6C)alkylamino, pyridyl,        imidazolyl, pyridyl-(1–6C)alkyl, imidazolyl-(1–6C)alkyl,        pyridyl-(1–6C)alkoxy, imidazolyl-(1–6C)alkoxy, pyrrolidinyl,        piperidinyl, morpholinyl, piperazinyl, 4-(1–6C)alkylpiperazinyl,        homopiperazinyl, 4-(1–6C)alkylhomopiperazinyl,        4-(2–6C)alkanoylpiperazinyl, pyrrolidinyl-(1–6C)alkyl,        piperidinyl-(1–6C)alkyl, morpholinyl-(1–6C)alkyl,        piperazinyl-(1–6C)alkyl, 4-(1–6C)alkylpiperazinyl-(1–6C)alkyl,        4-(2–6C)alkanoylpiperazinyl-(1–6C)alkyl, pyrrolidinyloxy,        piperidinyloxy, 1-(1–6C)alkylpiperidinyloxy,        pyrrolidinyl-(2–6C)alkoxy, piperidinyl-(2–6C)alkoxy,        morpholinyl-(2–6C)alkoxy, piperazinyl-(2–6C)alkoxy,        4-(1–6C)alkylpiperazinyl-(2–6C)alkoxy or        4-(2–6C)alkanoylpiperazinyl-(2–6C)alkoxy; and X, R², R³, Q, n        and q as appropriate have any of the meanings defined        hereinbefore or in this section relating to particular novel        compounds of the invention;    -   (r) m is 1 and R¹ is hydroxy, halogeno, trifluoromethyl, cyano.        mercapto, nitro, carboxy, (1–6C)alkoxycarbonyl, (1–6C)alkyl or        (1–6C)alkoxy; and X, R², R³, Q, n and q as appropriate have any        of the meanings defined hereinbefore or in this section relating        to particular novel compounds of the invention;    -   (s) m is 2 and the first R¹ substituent is selected from the        substituents specified in paragraph (q) hereinbefore and the        second R¹ substituent is selected from the substituents        specified in paragraph (r) hereinbefore; and X, R², R³, Q, n and        q as appropriate have any of the meanings defined hereinbefore        or in this section relating to particular novel compounds of the        invention; and    -   (t) X is —NHCO—; and R¹, R², R³, Q, m, n and q as appropriate        have any of the meanings defined hereinbefore or in this section        relating to particular novel compounds of the invention.

A preferred compound of the invention is an amide derivative of theFormula Ib wherein R³ is hydrogen, methyl or ethyl;

m is 0, 1 or 2;

R¹ is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl,ethyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino,diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl,diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy,2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy,2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy,3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino,2-methylaminoethylamino, 2-ethylaminoethylamino,3-methylaminopropylamino, 3-ethylaminopropylamino,2-dimethylaminoethylamino, 2-diethylaminoethylamino,3-dimethylaminopropylamino, 3-diethylaminopropylamino,N-(2-aminoethyl)-N-methylamino, N-(3-aminopropyl)-N-methylamino,N-(2-methylaminoethyl)N-methylamino,N-(2-ethylaminoethyl)-N-methylamino,N-(3-methylaminopropyl)N-methylamino,N-(3-ethylaminopropyl)-N-methylamino,N-(2-dimethylaminoethyl)N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)N-methylamino,N-(3-diethylaminopropyl)-N-methylamino, pyridyl, pyridylmethyl,pyridylmethoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,4-methylpiperazinyl, homopiperazinyl, 4-methylhomopiperazinyl,4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl,morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinylmethyl,4-acettkouoerazubtknetgtkm otrrikudubtkixtm 1methylpyrrolidinyloxy,piperidinyloxy, 1-methylpiperidinyloxy, 2-(pyrrolidinyl)ethoxy,3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy,2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinyl)ethoxy,3-(piperazinyl)propoxy, 2-(4-methylpiperazinyl)ethoxy,3-(4-methylpiperazinyl)propoxy, 2-(4-acetylpiperazinyl)ethoxy or3-(4-acetylpiperazinyl)propoxy;n is 0 or 1;R² is fluoro, chloro, bromo, methyl or ethyl;q is 0; andQ is phenyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl,pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl,benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl,isoquinolyl, quinazolinyl, quinoxalinyl or naphthyridinyl whichoptionally bears 1 or 2 substituents selected from hydroxy, fluoro,chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy,methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino,aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl,diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy,2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy,3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy,3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy,2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy,pyridyl, pyridylmethyl, pyridylmethoxy, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, 4-methylpiperazinyl, homopiperazinyl,4-methylhomopiperazinyl, 4-acetylpiperazinyl, pyrrolidinylmethyl,piperidinylmethyl, morpholinylmethyl, piperazinylmethyl,4-methylpiperazinylmethyl, 4-acetylpiperazinylmethyl, pyrrolidinyloxy,1-methylpyrrolidinyloxy, piperidinyloxy, 1-methylpiperidinyloxy,2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy,3-(piperidinyl)propoxy, 2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy,2-(piperazinyl)ethoxy, 3-(piperazinyl)propoxy,2-(4-methylpiperazinyl)ethoxy, 3-(4-methylpiperazinyl)propoxy,2-(4-acetylpiperazinyl)ethoxy and 3-(4-acetylpiperazinyl)propoxy; or apharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is an amide derivative ofthe Formula Ia wherein X is —NHCO— or —CONH—;

-   -   R¹ is hydrogen, methyl or ethyl;    -   m is 0,or 2;    -   R¹ is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano,        methyl, ethyl, methoxy, ethoxy, amino, methylamino, ethylamino,        dimethylamino, diethylamino, methylaminomethyl,        ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl,        2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy,        2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy,        2-dimethylaminoethoxy, 2-diethylaminoethoxy,        3-dimethylaminopropoxy, 3-diethylaminopropoxy,        2-aminoethylamino, 3-aminopropylamino, 2-methylaminoethylamino,        2-ethylaminoethylamino, 3-methylaminopropylamino,        3-ethylaminopropylamino, 2-dimethylaminoethylamino,        2-diethylaminoethylamino, 3-dimethylaminopropylamino,        3-diethylaminopropylamino, N-(2-aminoethyl)N-methylamino,        N-(3-aminopropyl)-N-methylamino,        N-(2-methylaminoethyl)N-methylamino,        N-(2-ethylaminoethyl)-N-methylamino,        N-(3-methylaminopropyl)N-methylamino,        N-(2-ethylaminopropyl)-N-methylamino,        N-(2-dimethylaminoethyl)N-methylamino,        N-(2-diethylaminoethyl)-N-methylamino,        N-(2-dimethylaminopropyl)N-methylamino,        N-(3-diethylaminopropyl)-N-methylamino, pyridyl, pyridylmethyl,        pyridylmethoxy, 3-pyrrolinyl, pyrrolidinyl, piperidinyl,        homopiperidinyl, morpholinyl, piperazinyl, 4-methylpiperazinyl,        4-ethylpiperazinyl, homopiperazinyl, 4-methylhomopiperazinyl,        4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl,        morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinylmethyl,        homopiperazinylmethyl, 4-methylhomopiperazinylmethyl,        4-acetylpiperazinylmethyl, pyrrolidinyloxy,        1-methylpyrrolidinyloxy, piperidinyloxy, 1-methylpiperidinyloxy,        homopiperidinyloxy, 1-methylhomopiperidinyloxy,        2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)propoxy,        2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy,        2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy,        2-(piperazinyl)ethoxy, 3-(piperazinyl)propoxy,        2-(4-methylpiperazinyl)ethoxy, 3-(4-methylpiperazinyl)propoxy,        2-(4-acetylpiperazinyl)ethoxy, 3-(4-acetylpiperazinyl)propoxy,        3-dimethylaminopropylaminomethyl,        3-dimethylamino-2,2-dimethylpropylaminomethyl,        2-(1-methylpyrrolidinylethyl)aminomethyl,        3-pyrrolidinylpropylaminomethyl, 2-morpholinylethylaminomethyl,        3-morpholinylpropylaminomethyl, 2-piperazinylethylaminomethyl,        3-(4-methylpiperazinylpropyl)aminomethyl, pyridylmethoxy,        imidazolylmethoxy, thiazolylmethoxy and        2-methylthiazolylmethoxy;        n is 0 or 1;        R² is fluoro, chloro, bromo, methyl or ethyl;        q is 0; and        Q is phenyl, indenyl, indanyl, tetrahydronaphthyl, fluorenyl,        furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl,        thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl,        pyrazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl,        benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl,        quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl,        naphthyridinyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl or        xanthenyl which optionally bears 1 or 2 substituents selected        from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino,        methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy,        cyclopentyloxy, methylenedioxy, methylamino, ethylamino,        dimethylamino, diethylamino, acetamido, propionamido,        N-methylacetamido, methanesulphonamido,        N-methylmethanesulphonamido, aminomethyl, methylaminomethyl,        ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl,        2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy,        2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy,        2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy,        2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy,        2-dimethylaminoethoxy, 2-diethylaminoethoxy,        3-dimethylaminopropoxy, 3-diethylaminopropoxy, phenyl, furyl,        thienyl, pyridyl, pyridylmethyl, pyridylmethoxy, azetidinyl,        3-pyrrolinyl, pyrrolidinyl, piperidinyl, homopiperidinyl,        morpholinyl, piperazinyl, 4-methylpiperazinyl, homopiperazinyl,        4-methylhomopiperazinyl, 4-acetylpiperazinyl,        pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl,        piperazinylmethyl, 4-methylpiperazinylmethyl,        4-acetylpiperazinylmethyl, pyrrolidinyloxy,        1-methylpyrrolidinyloxy, piperidinyloxy, 1-methylpiperidinyloxy,        2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)propoxy, 2-(piperidinyl        )ethoxy, 3-(piperidinyl)propoxy, 2-(morpholinyl)ethoxy,        3-(morpholinyl)propoxy, 2-(piperazinyl)ethoxy,        3-(piperazinyl)propoxy, 2-(4-methylpiperazinyl)ethoxy,        3-(4-methylpiperazinyl)propoxy, 2-(4-acetylpiperazinyl)ethoxy        and 3-(4-acetylpiperazinyl)propoxy, and wherein any phenyl,        furyl, thienyl, pyridyl or heterocyclyl group in a substituent        on Q may optionally bear 1 or 2 substituents selected from        fluoro, chloro, methyl and methoxy;        or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is an amide derivative ofthe Formula Ib wherein R³ is hydrogen or methyl;

m is 0,1 or 2;

R¹ is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl,ethyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino,diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl,diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy,2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy,2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy,3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino,2-methylaminoethylamino, 2-ethylaminoethylamino,3-methylaminopropylamino, 3-ethylaminopropylamino,2-dimethylaminoethylamino, 2-diethylaminoethylamino,3-dimethylaminopropylamino, 3-diethylaminopropylamino,N-(2-aminoethyl)-N-methylamino, N-(3-aminopropyl)-N-methylamino,N-(2-methylaminoethyl)N-methylamino,N-(2-ethylaminoethyl)-N-methylamino,N-(3-methylaminopropyl)N-methylamino,N-(3-ethylaminopropyl)-N-methylamino,N-(2-dimethylaminoethyl)N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)N-methylamino,N-(3-diethylaminopropyl)-N-methylamino, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy,4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino,piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl,4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl,piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy,1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,1-methylpiperidin-4-yloxy, 2-(pyrrolidin-1-yl)ethoxy,3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy or3-(4-acetylpiperazin-1-yl)propoxy;n is 0 or 1;R² is fluoro, chloro or methyl;q is 0; andQ is phenyl. 2-furyl. 2-thienyl, 4-oxazolyl, 5-isoxazolyl, 4-thiazolyl,5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-benzofuranyl,2-indolyl, 2-benzothienyl, 2-benzoxazolyl, 2-benzimidazolyl,2-benzothiazolyl, 4-benzofurazanyl, 2-quinolyl, 6-quinolyl, 7-quinolyl,3-isoquinolyl, 6-quinazolinyl, 7-quinazolinyl, 6-quinoxalinyl or7-quinoxalinyl which optionally bears 1 or 2 substituents selected fromhydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl,methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino,diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl,dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy,3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy,3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy,2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy,2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy,3-diethylaminopropoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy,4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino,piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl,4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl,piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy,1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,1-methylpiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy and3-(4-acetylpiperazin-1-yl)propoxy;or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is an amide derivative ofthe Formula Ib wherein R³ is hydrogen or methyl;

m is 0, 1 or 2;

R¹ is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl,ethyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino,diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl,diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy,2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylanminopropoxy,2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy,3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino,2-methylaminoethylamino, 2-ethylaminoethylamino,3-methylaminopropylamino, 3-ethylaminopropylamino,2-dimethylaminoethylamino, 2-diethylaminoethylamino,3-dimethylaminopropylamino, 3-diethylaminopropylamino, N-(2-aminoethyl)N-methylamino, N-(3-aminopropyl)-N-methylamino,N-(2-methylaminoethyl)N-methylamino,N-(2-ethylaminoethyl)-N-methylamino,N-(3-methylaminopropyl)N-methylamino,N-(3-ethylaminopropyl)-N-methylamino,N-(2-dimethylaminoethyl)N-methylamino,N-(2-diethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)N-methylamino, N-(3-diethylaminopropyl)-N-methylamino, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy,4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino,piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl,4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl,pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl,piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy,1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,1-methylpiperidin-4-yloxy, 2-(pyrrolidin-1-yl)ethoxy,3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy or3-(4-acetylpiperazin-1-yl)propoxy;n is 0 or 1;R² is fluoro, chloro or methyl;q is 0; andQ is phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl which optionally bears 1or 2 substituents selected from hydroxy, fluoro, chloro,trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy,methylenedioxy, methylamino, ethylamino. dimethylamino, diethylamino,aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl,diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy,2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy,3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy,3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy,2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl,4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy,pyrrolidin-1-yl, piperidino. morpholino, piperazin-1-yl,4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl,4-acetylpiperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl,morpholinomethyl, piperazin-]-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy,1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,1-methylpiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy,3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy,3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy,3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy and3-(4-acetylpiperazin-1-yl)propoxy;or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is an amide derivative ofthe Formula Ib wherein R³ is hydrogen or methyl;

m is 1 or 2;

R¹ is hydroxy, fluoro, chloro, methyl, methoxy, dimethylaminomethyl,diethylaminomethyl, 2-dimethylaminoethoxy, 2-diethylaminoethoxy,3-dimethylaminopropoxy, 3-diethylaminopropoxy,3-dimethylamino-2-hydroxypropoxy, 3-diethylamino-2-hydroxypropoxy,2-aminoethylamino, 3-aminopropylamino, 4-aminobutylamino,3-methylaminopropylamino, 2-dimethylaminoethylamino,2-diethylaminoethylamino, 3-dimethylaminopropylamino,4-dimethylaminobutylamino, 3-amino-2-hydroxypropylamino,3-dimethylamino-2-hydroxypropylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino,piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl,4-ethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl,homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl,4-methylhomopiperazin-1-ylmethyl, morpholinomethyl,3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl,4-(2-hydroxyethyl)piperazin-1-ylmethyl, pyrrolidin-3-yloxy,1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,1-methylpiperidin-4-yloxy, 1-benzylpiperidin-4-yloxy,2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy,3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy,2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy,2-hydroxy-3-pyrrolidin-1-ylpropoxy, 2-hydroxy-3-piperidinopropoxy,2-hydroxy-3-morpholinopropoxy, piperidin-4-ylamino,1-methylpiperidin-4-ylamino, 1-benzylpiperidin-4-ylamino,2-pyrrolidin-1-ylethylamino, 3-pyrrolidin-1 ylpropylamino,2-morpholinoethylamino, 3-morpholinopropylamino, 2-piperidinoethylamino,3-piperidinopropylamino, 2-piperazin-1-ylethylamino,3-piperazin-1-ylpropylamino, 2-(4-methylpiperazin-1-yl)ethylamino,3-(4-methylpiperazin-1-yl)propylamino,2-(1-methylpyrrolidin-2-yl)ethylamino,3-(1-methylpyrrolidin-2-yl)propylamino, 2-dimethylaminoethylaminomethyl,3-dimethylaminopropylaminomethyl,3-dimethylamino-2,2-dimethylpropylaminomethyl,2-(1-methylpyrrolidin-2-ylethyl)aminomethyl,3-pyrrolidin-1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl,3-morpholinopropylaminomethyl, 2-piperazin-1-ylethylaminomethyl,3-(4-methylpiperazin-1-ylpropyl)aminomethyl or 2-pyridylmethoxy;n is O or 1;R² is chloro or methyl;q is 0; andQ is 2-pyridyl, 3-pyridyl or 4-pyridyl which bears a substituentselected from pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl,2-hydroxymethylpyrrolidin-1-yl, morpholino, piperidino,4-hydroxypiperidin-1-yl, piperazin-1-yl and 4-methylpiperazin-1-yl;or a pharmaceutically-acceptable salt thereof.

An especially preferred compound of the invention is an amide derivativeof the Formula Ib wherein R³ is hydrogen or methyl;

m is 1 and R¹ is selected from diethylaminomethyl,N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino,piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl,4-ethylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl,piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-methylhomopiperazin-1-ylmethyl, morpholinomethyl,3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl,pyrrolidin-3-yloxy, piperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy,2-piperidinoethoxy, 2-morpholinoethoxy,3-dimethylaminopropylaminomethyl,3-dimethylamino-2,2-dimethylpropylaminomethyl,2-(1-methylpyrrolidin-2-ylethyl)aminomethyl,3-pyrrolidin-1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl.3-morpholinopropylaminomethyl, 2-piperazin-1-ylethylaminomethyl,3-(4-methylpiperazin-1-ylpropyl)aminomethyl and 2-pyridylmethoxy;n is 0 or 1;R² is methyl;q is 0; andQ is 3-pyridyl or 4-pyridyl which bears a substituent selected frompyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl and4-methylpiperazin-1-yl;or a pharmaceutically-acceptable salt thereof.

A further especially preferred compound of the invention is an amidederivative of the Formula Ib wherein R¹ is hydrogen or methyl;

m is 1 and R¹ is selected from diethylaminomethyl,N-(3-dimethylaminopropyl)N-methylamino, 3-pyrrolin-1-yl,pyrrolidin-1-yl, morpholino, piperidino, homopiperidin-1-yl,piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl,homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl,4-methylhomopiperazin-1-ylmethyl, morpholinomethyl,3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl,pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, piperidin-4-yloxy,N-methylpiperidin-4-yloxy, homopiperidin-4-yloxy,N-methylhomopiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy,2-piperidinoethoxy, 2-morpholinoethoxy,3-dimethylaminopropylaminomethyl,3-dimethylamino-2,2-dimethylpropylaminomethyl,2-(1-methylpyrrolidin2-ylethyl)aminomethyl,3-pyrrolidin-1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl,3-morpholinopropylaminomethyl, 2-piperazin1-ylethylaminomethyl,3-(4-methylpiperazin-1-ylpropyl)aminomethyl, 2-pyridylmethoxy,4-thiazolylmethoxy and 2-methylthiazol-4-ylmethoxy;n is 0 or 1;R² is methyl;q is 0; andQ is phenyl which bears 1 or 2 substituents selected from fluoro,chloro, trifluoromethyl, methoxy, cyclopentyloxy, acetamido,N-methylmethanesulphonamido, 2-furyl, azetidin-1-yl, 3-pyrrolin-1-yl,pyrrolidin-1-yl, morpholino piperidino, homopiperidin-1-ylpiperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl and4-methylhomopiperazin-1-yl or Q is 1-fluorenyl or 4-dibenzofuranyl, or Qis 3-pyridyl or 4-pyridyl which bears a substituent selected fromazetidin-1-yl, 3-pyrrolin-1-yl, pyrrolidin-1-yl, morpholino, piperidino,homopiperidino, piperazin-1-yl, homopiperazin-1-yl,4-methylpiperazin-1-yl and 4-methylhomopiperazin-1-yl;or a pharmaceutically-acceptable salt thereof.

A further especially preferred compound of the invention is an amidederivative of the Formula Ib wherein R³ is hydrogen or methyl;

m is 1 and R¹ is 4-methylpiperazin-1-yl orN-(3-dimethylaminopropyl)-N-methylamino;

n is 0 or 1;

R² is 6-methyl;

q is 0; and

Q is 2-morpholinopyrid-4-yl;

or a pharmaceutically-acceptable salt thereof.

A further especially preferred compound of the invention is an amidederivative of the Formula Ib wherein R³ is hydrogen or methyl;

m is 1 and R¹ is 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl orN-(3-dimethylaminopropyl)-N-methylamino;

n is 0 or 1;

R¹ is 6-methyl;

q is 0; and

Q is 2-pyrrolidin-1-ylpyrid-4-yl, 2-(3-pyrrolin-1-yl)pyrid-4-yl,2-piperidinopyrid-4-yl, 2-morpholinopyrid-4-yl, 1-fluorenyl,dibenzofuran-4-yl, 3-acetamidophenyl or 3-(2-furyl)phenyl;

or a pharmaceutically-acceptable salt thereof.

A further especially preferred compound of the invention is an amidederivative of the Formula Ib wherein R³ is hydrogen;

m is 1 and R¹ is piperazin-1-yl, 4-methylpiperazin-1-yl,4-methylhomopiperazin-1-yl or N-(3-dimethylaminopropyl)-N-methylamino;

n is 0 or 1;

R² is 6-methyl or 6-fluoro;

q is 0; and

Q is 2-azetidin-1-ylpyrid-4-yl, 2-pyrrolidin-1-ylpyrid-4-yl,2-(3-pyrrolin-1-yl)pyrid-4-yl, 2-piperidinopyrid-4-yl,2-morpholinopyrid-4-yl-1-fluorenyl, dibenzofuran-4-yl,5-(4-chlorophenyl)furan-2-yl, 4-(4-chlorophenyl)thien-2-yl,2-methoxyphenyl, 3-ethoxyphenyl, 3-(1,1,2,2-tetrafluoroethoxy)phenyl,3,4-methylenedioxyphenyl, 3-acetamidophenyl, 3-(4-fluorophenyl)phenyl,3-(2-furyl)phenyl, 3-fluoro-5-pyrrolidin-1-ylphenyl,3-fluoro-5-piperidinophenyl, 3-fluoro-5-morpholinophenylor 3-morpholino-5-trifluoromethylphenyl;or a pharmaceutically-acceptable salt thereof.

A particular preferred compound of the invention is, for example6-[N-(3-dimethylaminopropyl)-N-methylamino]-2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3,4-dihydroquinazolin-4-one,6-[-(3-dimethylaminopropyl)-N-methylamino]-2-methyl-3-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3,4-dihydroquinazolin-4-one,6-[N-(3-dimethylaminopropyl)-N-methylamino]-3-[5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3,4-dihydroquinazolin-4-one,6-(4-methylpiperazin-1-yl)-3-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3,4-dihydroquinazolin-4-oneor8-[-(3-dimethylaminopropyl)-N-methylamino]-3-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3,4-dihydroquinazolin-4-one;

or a pharmaceutically-acceptable salt thereof.

A further particular preferred compound of the invention is, for example3-[2-methyl-5-(2-pyrrolidin-1-ylpyrid-4-ylcarbonylamino)phenyl]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one,3-[2-methyl-5-(2-piperidinopyrid-4-ylcarbonylamino)phenyl]6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one,3-{2-methyl-5-[2-(3-pyrrolin-1-yl)pyrid-4-ylcarbonylamino]phenyl}6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one,3-[5-dibenzofuran-4-ylcarbonylamino-2-methylphenyl]-6-(4-methylpiperazin-1-yl)3,4-dihydroquinazolin-4-one,3-{5-[3-(⁹-furyl)benzamido]-2-methylphenyl1-6-(4-methylpiperazin-1-yl)3.4-dihydroquinazolin-4-one or3-[5-(3-acetamidobenzamido]-2-methylphenyl}-6-(4-methylpiperazin-1-yl)3,4-dihydroquinazolin-4-one, or apharmaceutically-acceptable salt thereof.

An amide derivative of the Formula Ia or Ib, or apharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, maybe prepared by any process known to be applicable to the preparation ofchemically-related compounds. Such processes, when used to prepare anovel amide derivative of the Formula Ia or Ib are provided as a furtherfeature of the invention and are illustrated by the followingrepresentative process variants in which, unless otherwise stated, X,R¹, R², R³, m, n, q and Q have any of the meanings defined hereinbefore.Necessary starting materials may be obtained by standard procedures oforganic chemistry. The preparation of such starting materials isdescribed in conjunction with the following representative processvariants and within the accompanying Examples. Alternatively necessarystarting materials are obtainable by analogous procedures to thoseillustrated which are within the ordinary skill of an organic chemist.(a) A compound of the Formula Ia, or a pharmaceutically-acceptable saltor in-vivo-cleavable ester thereof, may be prepared by reacting anN-phenyl-2-aminobenzamide of the

with a carboxylic acid of the Formula III, or a reactive derivativethereof,

wherein variable groups are as defined hereinbefore and wherein anyfunctional group is protected if necessary, and:

-   -   (i) removing any protecting groups, and    -   (ii) optionally forming a pharmaceutically-acceptable salt or        in-vivo-cleavable ester.

A suitable reactive derivative of a carboxylic acid of the Formula IIIis, for example, an acyl halide, for example an acyl chloride formed bythe reaction of the acid and an inorganic acid chloride, for examplethionyl chloride; a mixed anhydride, for example an anhydride formed bythe reaction of the acid and a chloroformate such as isobutylchloroformate; an active ester, for example an ester formed by thereaction of the acid with a phenol such as pentafluorophenol, with anester such as pentafluorophenol trifluoroacetate or with an alcohol suchas N-hydroxybenzotriazole; an acyl azide, for example an azide formed bythe reaction of the acid and an azide such as diphenylphosphoryl azide;an acyl cyanide, for example a cyanide formed by the reaction of an acidand a cyanide such as diethylphosphoryl cyanide; or the product of thereaction of the acid and a carbodiimide such asdicyclohexylcarbodiimide. A preferred reactive derivative of acarboxylic acid of the Formula III is, for example, an ester of thecorresponding ortho acid of the carboxylic acid of the Formula III, forexample a trialkyl ester such as a trimethyl or triethyl ester. For acarboxylic acid of the Formula III wherein R³ is hydrogen, a suitableortho acid ester is triethyl orthoformate and for a carboxylic acid ofthe Formula III wherein R³ is methyl, a suitable ortho acid ester istriethyl orthoacetate.

The reaction may conveniently be carried out in the presence of asuitable base such as, for example, an alkali or alkaline earth metalcarbonate, alkoxide, hydroxide or hydride, for example sodium carbonate,potassium carbonate, sodium ethoxide, potassium butoxide, sodiumhydroxide, potassium hydroxide, sodium hydride or potassium hydride, oran organometallic base such as an alkyl-lithium, for examplen-butyl-lithium, or a dialkylamino-lithium, for example lithiumdi-isopropylamide, or, for example, an organic amine base such as, forexample, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, morpholine or diazabicyclo[5.4.0]undec-7-ene.

The reaction may also conveniently be carried out in the presence of asuitable acid such as, for example, an inorganic or organic acid such ashydrochloric, hydrobromic, sulphuric, acetic, trifluoroacetic, citric ormaleic acid.

The reaction is also preferably carried out in a suitable inert solventor diluent, for example methanol, ethanol, tetrahydrofuran, methylenechloride, 1,2-dimethoxyethane, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide oracetone, and at a temperature in the range, for example, 0 to 150° C.,conveniently at or near 75° C.

Protecting groups may in general be chosen from any of the groupsdescribed in the literature or known to the skilled chemist asappropriate for the protection of the group in question and may beintroduced by conventional methods. Protecting groups may be removed byany convenient method as described in the literature or known to theskilled chemist as appropriate for the removal of the protecting groupin question, such methods being chosen so as to effect removal of theprotecting group with minimum disturbance of groups elsewhere in themolecule.

Specific examples of protecting groups are given below for the sake ofconvenience, in which “lower”, as in, for example, lower alkyl,signifies that the group to which it is applied preferably has 1–4carbon atoms. It will be understood that these examples are notexhaustive. Where specific examples of methods for the removal ofprotecting groups are given below these are similarly not exhaustive.The use of protecting groups and methods of deprotection notspecifically mentioned is of course within the scope of the invention.

A carboxy protecting group may be the residue of an ester-formingaliphatic or arylatiphatic alcohol or of an ester-forming silanol (thesaid alcohol or silanol preferably containing 1–20 carbon atoms).Examples of carboxy protecting groups include straight or branched chain(1–12C)alkyl groups (for example isopropyl, tert-butyl); lower alkoxylower alkyl groups (for example methoxymethyl, ethoxymethyl,isobutoxymethyl); lower aliphatic acyloxy lower alkyl groups, (forexample acetoxymethyl, propionyloxymethyl, butyryloxymethyl,pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (forexample 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl loweralkyl groups (for example benzyl, p-methoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups(for example trimethylsilyl and tert-butyldimethylsilyl); tri(loweralkyl)silyl lower alkyl groups (for example trimethylsilylethyl); and(2–6C)alkenyl groups (for example allyl and vinylethyl). Methodsparticularly appropriate for the removal of carboxyl protecting groupsinclude for example acid-, base-, metal- or enzymically-catalysedhydrolysis.

Examples of hydroxy protecting groups include lower alkyl groups (forexample tert-butyl), lower alkenyl groups (for example allyl); loweralkanoyl groups (for example acetyl). lower alkoxycarbonyl groups (forexample tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (forexample allyloxycarbonyl); aryl lower alkoxycarbonyl groups (for examplebenzoyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyln-nitrobenzyloxycarbonyl); tri lower alkylsilyl (for exampletrimethylsilyl, tert-butyldimethylsilyl) and aryl lower alkyl (forexample benzyl) groups.

Examples of amino protecting groups include formyl, aralkyl groups (forexample benzyl and substituted benzyl, p-methoxybenzyl, nitrobenzyl and2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl andfurylmethyl groups; lower alkoxycarbonyl (for exampletert-butoxycarbonyl); lower alkenyloxycarbonyl (for exampleallyloxycarbonyl); aryl lower alkoxycarbonyl groups (for examplebenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl; trialkylsilyl (for example trimethylsislyl andtert-butyldimethylsilyl); alkylidene (for example methylidene);benzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groupsinclude, for example, acid-, base-, metal- or enzymically-catalysedhydrolysis for groups such as p-nitrobenzyloxycarbonyl, hydrogenationfor groups such as benzyl and photolytically for groups such aso-nitrobenzyloxycarbonyl.

The reader is referred to Advanced Organic Chemistry, 4th Edition, byJerry March, published by John Wiley & Sons 1992,for general guidance onreaction conditions and reagents. The reader is referred to ProtectiveGroups in Organic Synthesis, 2nd Edition, by Green et al., published byJohn Wiley & Sons for general guidance on protecting groups.

The N-phenyl-2-aminobenzamide of the Formula II may be prepared byreduction of the corresponding nitro compound of the Formula IV

Typical reaction conditions include the use of ammonium formate orhydrogen gas in the presence of a catalyst, for example a metalliccatalyst such as palladium-on-carbon. Alternatively a dissolving metalreduction may be carried out, for example using iron in the presence ofan acid, for example an inorganic or organic acid such as hydrochloric,hydrobromic, sulphuric or acetic acid. The reaction is convenientlycarried out in the presence of an organic solvent (preferably a polarprotic solvent) and preferably with heating, for example to about 60° C.Any) functional groups are protected and deprotected as necessary.

The nitrobenzene of the Formula IV wherein X is —NHCO— may be preparedby the reaction of the aniline of the Formula V

with a carboxylic acid of the Formula VI, or a reactive derivativethereof as defined hereinbefore,HO₂C—(CH₂)_(q)—Q  VIunder standard amide bond forming conditions, wherein variable groupsare as defined hereinbefore and wherein any functional group isprotected if necessary.

Typical conditions include activating the carboxy group of the compoundof Formula VI, for example by treatment with a halo reagent (for exampleoxalyl chloride) to form an acyl halide in an organic solvent at ambienttemperature and then reacting the activated compound with the aniline ofFormula V. Any functional groups are protected and deprotected asnecessary. Conveniently a carbodiimide coupling reagent is used in thepresence of an organic solvent (preferably an anhydrous polar aproticorganic solvent) at a non-extreme temperature, for example in the region-10 to 40° C., typically at ambient temperature of about 20° C.

An aniline of the Formula V may be prepared by the reaction of a benzoicacid of Formula VII, or an activated derivative thereof as definedhereinbefore,

with an aniline of Formula VIII

under suitable amide bond forming conditions as defined hereinbefore.

The nitrobenzene of Formula IV wherein X is —NHCO— may also be preparedby the reaction of a benzoic acid of Formula VII, or an activatedderivative thereof as defined hereinbefore, with an aniline of FormulaIX

under suitable amide bond forming conditions as defined hereinbefore.

Corresponding reactions as illustrated in the Examples are used toprepare the nitrobenzene of the Formula IV wherein X is —CONH—.

-   -   (b) A compound of the Formula Ia wherein X is —NHCO—, or a        pharmaceutically-acceptable salt or in-vivo-cleavable ester        thereof, may be prepared by reacting an aniline of        with a carboxylic acid of the Formula VI, or a reactive        derivative thereof as defined hereinbefore,        under standard amide bond forming conditions as defined        hereinbefore, wherein variable groups are as defined        hereinbefore and wherein any functional group is protected if        necessary, and:    -   (i) removing any protecting groups; and        (ii) optionally forming a pharmaceutically-acceptable salt-or        in-vivo-cleavable ester.

The reaction is preferably carried out in the presence of a suitablebase as defined hereinbefore The reaction is preferably carried out in asuitable inert solvent or diluent, for example tetrahydrofuran.methylene chloride, 1,2-dimethoxyethane, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide oracetone, and at a temperature in the range, for example, -78 to 150° C.,conveniently at or near ambient temperature.

Typically a carbodiimide coupling reagent is used in the presence of anorganic solvent (preferably an anhydrous polar aprotic organic solvent)at a non-extreme temperature, for example in the region -10 to 40° C.,typically at ambient temperature of about 20° C.

An aniline of the Formula X may be prepared by reduction under standardconditions as defined hereinbefore of the corresponding nitro compoundof the Formula XI

-   -   The nitro compound of the Formula XI may be prepared by reacting        an N-phenyl-2-aminobenzamide of the Formula XII        with a carboxylic acid of the Formula III, or a reactive        derivative thereof,        wherein variable groups are as defined hereinbefore and wherein        any functional group is protected if necessary    -   (c) A compound of the Formula Ia wherein R¹ or a substituent on        Q is (1–6C)alkoxy or substituted (1–6C)alkoxy, (1–6C)alkylthio,        (1–6C)alkylamino, di-[(1–6C)alkyl]amino or substituted        (1–6C)alkylamino may be prepared by the alkylation, conveniently        in the presence of a suitable base as defined hereinbefore, of        an amide derivative of the Formula Ia wherein R¹ or a        substituent on Q is hydroxy, mercapto or amino as appropriate.

The reaction is preferably carried out in the presence of a suitableinert solvent or diluent, for example a halogenated solvent such asmethylene chloride, chloroform or carbon tetrachloride, an ether such astetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or adipolar aprotic solvent such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide.The reaction is conveniently carried out at a temperature in the range,for example, 10 to 1 50° C., preferably in the range 20 to 80° C.

A suitable alkylating agent is, for example, any agent known in the artfor the alkylation of hydroxy to alkoxy or substituted alkoxy, or forthe alkylation of mercapto to alkylthio, or for the alkylation of aminoto alkylamino or substituted alkylamino, for example an alkyl orsubstituted alkyl halide, for example a (1–6C)alkyl chloride, bromide oriodide or a substituted (1–6C)alkyl chloride, bromide or iodide, in thepresence of a suitable base as defined hereinbefore, in a suitable inertsolvent or diluent as defined hereinbefore and at a temperature in therange, for example, 10 to 1 40° C., conveniently at or near ambienttemperature.

-   -   (d) A compound of the Formula Ia wherein a substituent on Q is        amino, (1–6C)alkylamino, di-[(1–6C)alkyl]amino, substituted        (1–6C)alkylamino, substituted N-(1–6C)alkyl-(2–6C)alkylamino or        a N-linked heterocyclyl group may be prepared by the reaction,        conveniently in the presence of a suitable base as defined        hereinbefore, of an amide derivative of the Formula Ia wherein a        substituent on Q is a suitable leaving group with an appropriate        amine.

A suitable leaving group is, for example, a halogeno group such asfluoro, chloro or bromo, a (1–6C)alkanesulphonyloxy group such asmethanesulphonyloxy or an arylsulphonyloxy group such as4-toluenesulphonyloxy.

The reaction is conveniently carried out in the presence of a suitableinert diluent or carrier as defined hereinbefore and at a temperature inthe range, for example, 20 to 200° C., conveniently in the range 75 to 150° C.

-   -   (e) A compound of the Formula Ia wherein R¹ or a substituent on        Q is (1–6C)alkanoylamino or substituted (2–6C)alkanoylamino may        be prepared by the acylation of a compound of the Formula Ia        wherein R¹ or a substituent on Q is amino.

A suitable acylating agent is, for example, any agent known in the artfor the acylation of amino to acylamino, for example an acyl halide, forexample a (1–6C)alkanoyl chloride or bromide, conveniently in thepresence of a suitable base, as defined hereinbefore, an alkanoic acidarhydride or mixed anhydride, for example a (1–6C)alkanoic acidanhydride such as acetic anhydride or the mixed anhydride formed by thereaction of an alkanoic acid and a (1–6C)alkoxycarbonyl halide, forexample a (1–6C)alkoxycarbonyl chloride, in the presence of a suitablebase as defined hereinbefore. In general the acylation is carried out ina suitable inert solvent or diluent as defined hereinbefore and at atemperature, in the range, for example, −30 to 120° C., conveniently ator near ambient temperature.

-   -   (f) A compound of the Formula Ia wherein R¹ or a substituent on        Q is (1–6C)alkanesulphonylamino may be prepared by the reaction        of a compound of the Formula Ia wherein R¹ or a substituent on Q        is amino with a (1–6C)alkanesulphonic acid, or an activated        derivative thereof.

A suitable activated derivative of a (1–6C)alkanesulphonic acid is, forexample, an alkanesulphonyl halide, for example an alkanesulphonylchloride formed by the reaction of the sulphonic acid and an inorganicacid chloride, for example thionyl chloride. The reaction is preferablycarried out in the presence of a suitable base as defined hereinbefore,particularly pyridine, and in a suitable inert solvent or diluent asdefined hereinbefore, particularly methylene chloride.

-   -   (g) A compound of the Formula Ia wherein R¹ or a substituent on        Q is carboxy, carboxy-(1–6C)alkyl, carboxy-(1–6C)alkoxy,        carboxy-(1–6C)alkylamino, N-(1–6C)alkyl-carboxy-(1–6C)alkylamino        or carboxy-(2–6C)alkanoylamino may be prepared by the cleavage        of a compound of the Formula Ia wherein R¹ or a substituent on Q        is (1–6C)alkoxycarbonyl, (1–6C)alkoxycarbonyl-(1–6C)alkyl,        (1–6C)alkoxycarbonyl-(1–6C)alkoxy,        (1–6C)alkoxycarbonyl-(1–6C)alkylamino,        N-(1–6C)alkyl-(1–6C)alkoxycarbonyl-(1–6C)alkylamino or        (1–6C)alkoxycarbonyl-(2–6C)alkanoylamino as appropriate.

The cleavage reaction may conveniently be carried out by any of the manyprocedures known in the art for such a transformation. The reaction maybe carried out, for example, by hydrolysis under acidic or basicconditions. A suitable base is, for example, an alkali metal, alkalineearth metal or ammonium carbonate or hydroxide, for example sodiumcarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide orammonium hydroxide. The reaction is preferably carried out in thepresence of water and a suitable solvent or diluent such as methanol orethanol. The reaction is conveniently carried out at a temperature inthe range 10 to 1 50° C., preferably at or near ambient temperature.

-   -   (h) A compound of the Formula Ia wherein R¹ is        amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,        di-[(1–6C)alkyl]amino-(1–6C)alkyl or a heterocyclyl-(1–6C)alkyl        group may be prepared by the reaction, conveniently in the        presence of a suitable base as defined hereinbefore, of a        compound of the Formula XIII        wherein X, R², R³, n, q and Q have any of the meanings defined        hereinbefore and Z is a suitable leaving group with an        appropriate amine or heterocycle.

A suitable leaving group Z is, for example, a halogeno group such asfluoro, chloro or bromo, a (1–6C)alkanesulphonyloxy group such asmethanesulphonyloxy or an arylsulphonyloxy group such as4-toluenesulphonyloxy.

The reaction is conveniently carried out in the presence of a suitableinert diluent or, carrier as defined hereinbefore and at a temperaturein the range, for example, 20 to 200° C., conveniently in the range 50to 150° C.

The following biological assays and Examples serve to illustrate thepresent invention.

Biological Assays

The following assays can be used to measure the p38 kinase-inhibitory,the TNF-inhibitory and anti-arthritic effects of the compounds of thepresent invention:

In vitro enzyme assay

The ability of compounds of the invention to inhibit the enzyme p38kinase was assessed. Activity of test compounds against each of the p38αand p38β isoforms of the enzyme was determined.

Human recombinant MKK6 (GenBank Accesion Number G1209672) was isolatedfrom Image clone 45578 (Genomics, 1996, 33, 151) and utilised to produceprotein in the form of a GST fusion protein in a pGEX vector usinganalogous procedures to those disclosed by J. Han et al., Journal ofBiological Chemistry, 1996, 271, 2886–2891.p38α (GenBank AccessionNumber G529039) and p38β (GenBank Accession Number G1469305) wereisolated by PCR amplification of human lymphoblastoid cDNA (GenBankAccession Number GM 1416) and human foetal brain cDNA [synthesised frommRNA (Clontech, catalogue no. 6525-1) using a Gibco superscript cDNAsynthesis kit] respectively using oligonucleotides designed for the 5′and 3′ ends of the human p38α and p38P genes using analogous proceduresto those described by J. Han et al., Biochimica et Biophysica Acta,1995, 1265, 224–227 and Y. Jiang et al., Journal of BiologicalChemistry, 1996, 271, 17920–17926.

Both p38 protein isoforms were expressed in e. coli in PET vectors.Human recombinant p38α and p38β isoforms were produced as 5′ c-myc, 6Histagged proteins. Both MKK6 and the p38 proteins were purified usingstandard protocols: the GST MKK6 was purified using a glutathionesepharose column and the p38 proteins were purified using nickel chelatecolumns.

The p38 enzymes were activated prior to use by incubation with MKK6 for3 hours at 30° C. The unactivated coli-expressed MKK6 retainedsufficient activity to fully activate both isoforms of p38.Theactivation incubate comprised p38α (10 μl of 10 g/ml) or p38,β (10 μ1 )of 5 mg/ml) together with MKK6 (10 μl of 1 mg/ml), ‘Kinase buffer’ [100μ; pH 7.4 buffer comprising Tris (50 mM), EGTA (0.1 mM), sodiumorthovanadate (0.1 mM) and β-mercaptoethanol (0.1%)] and MgATP (30 μof50 mM Mg(OCOCH₃)₂ and 0.5mM ATP). This produced enough activated p38enzyme for 3 Microtiter plates.

Test compounds were solubilised in DMSO and 10 μl of a 1:10 dilutedsample in ‘Kinase Buffer’ was added to a well in a Microtiter plate. Forsingle dose testing, the compounds were tested at 10 μM. ‘Kinase AssayMix’ [30 μl; comprising Myelin Basic Protein (Gibco BRL cat. no.1322B-010; 1 ml of a 3.33 mg/ml solution in water), activated p38 enzyme(50 μl) and ‘Kinase Buffer’ (2ml)] was then added followed by ‘LabelledATP’ [10 μl; comprising 50 μM ATP, 0.1 μCi ³³P ATP (AmershamInternational cat. no. BF 1000) and 50 mM Mg(OCOCH₃)₂]. The plates wereincubated at room temperature with gentle agitation. Plates containingp38α were incubated for 90min and plates containing p38β were incubatedfor 45min. Incubation was stopped by the addition of 50 μl of 20%trichloroacetic acid (TCA). The precipitated protein was phosphorylatedby p38 kinase and test compounds were assessed for their ability toinhibit this phosphorylation. The plates were filtered using a CanberraPackard Unifilter and washed with 2% TCA, dried overnight and counted ona Top Count scintillation counter.

Test compounds were tested initially at a single dose and activecompounds were retested to allow IC₅₀ values to be determined.

In vitro cell-based assays

(i) PBMC

The ability of compounds of this invention to inhibit TNFα productionwas assessed by using human peripheral blood mononuclear cells whichsynthesise and secrete TNFα when stimulated with lipopolysaccharide.

Peripheral blood mononuclear cells (PBMC) were isolated from heparinised(10 units/ml heparin) human blood by density centrifugation(Lymphoprep™; Nycomed). Mononuclear cells were resuspended in culturemedium [RPMI 1640 medium (Gibco) supplemented with 50 units/mlpenicillin, 50 μg/ml streptomycin, 2 mM glutamine and 1%heat-inactivated human AB serum (Sigma H-1513)]. Compounds weresolubilised in DMSO at a concentration of 50 mM, diluted 1:100 inculture medium and subsequently serial dilutions were made in culturemedium containing 1% DMSO. PBMCs (2.4×10⁵ cells in 160 μl culturemedium) were incubated with 20 μl of varying concentrations of testcompound (triplicate cultures) or 20 μl culture medium containing 1%DMSO (control wells) for 30 minutes at 37° C. in a humidified (5%CO₂/95%air) incubator (Falcon 3072 ; 96 well flat-bottom tissue cultureplates), 20 μl lipopolysaccharide [LPS E. Coli 0111:B4 (Sigma L-4130),final concentration 10 μg/ml] solubilised in culture medium was added toappropriate wells. 20 μl culture medium was added to “medium alone”control wells. Six “LPS alone” and four “medium alone” controls wereincluded on each 96 well plate. Varying concentrations of a known TNFαinhibitor were included in each test, i.e. an inhibitor of the PDE TypeIV enzyme (for example see Semmler, J. Wachtel. H and Endres, S., Int.J. Immunopharmac. (1993), 15(3), 409–413) or an inhibitor of pro TNFαconvertase (for example, see McGeehan, G. M. et al. Nature (1994) 370,558–561). Plates were incubated for 7 hours at 37° C. (humidifiedincubator) after which 100 μl of the supernatant was removed from eachwell and stored at −70° C. (96 well round-bottom plates; Corning 25850).TNFα levels were determined in each sample using a human TNFα ELISA (seeWO92/10190 and Current Protocols in Molecular Biologv, vol 2 byFrederick M. Ausbel et al., John Wiley and Sons Inc.).${\%\mspace{14mu}{inhibition}} = {\frac{\begin{matrix}{\left( {{{LPS}\mspace{14mu}{alone}} - {{medium}\mspace{14mu}{alone}}} \right) -} \\\left( {{{test}\mspace{14mu}{concentration}} - {{medium}\mspace{14mu}{alone}}} \right)\end{matrix}}{\left( {{{LPS}\mspace{14mu}{alone}} - {{medium}\mspace{14mu}{alone}}} \right)} \times 100}$(ii) Human Whole Blood

The ability of the compounds of this invention to inhibit TNFαproduction was also assessed in a human whole blood assay. Human wholeblood secretes TNFα when stimulated with LPS. This property of bloodforms the basis of an assay which is used as a secondary test forcompounds which profile as active in the PBMC test.

Heparinised (10 units/ml) human blood was obtained from volunteers. 160μl whole blood were added to 96 well round-bottom plates (Corning25850). Compounds were solubilised and serially diluted in RPMI 1640medium (Gibco) supplemented with 50 units/ml penicillin, 50 μg/mlstreptomycin and 2 mM glutamine, as detailed above. 20 μl of each testconcentration was added to appropriate wells (triplicate cultures), 20μl of RPMI 1640 medium supplemented with antibiotics and glutamine wasadded to control wells. Plates were incubated for 30 minutes at 37° C.(humidified incubator), prior to addition of 20 μl LPS (finalconcentration 10 μg/ml). RPMI 1640 medium was added to control wells.Six “LPS alone” and four “medium alone” controls were included on eachplate. A known TNFα synthesis/secretion inhibitor was included in eachtest. Plates were incubated for 6 hours at 37° C. (humidifiedincubator). Plates were centrifuged (2000 rpm for 10 minutes) and 100 μlplasma removed and stored at −70° C. (Corning 25850 plates). TNFα levelswere measured by ELISA (see WO92/10190 and Current Protocols inMolecular Biology, vol 2 by Frederick M. Ausbel et al., John Wiley andSons Inc.). The paired antibodies that were used in the ELIZA wereobtained from R&D Systems (catalogue nos. MAB610 anti-human TNFA coatingantibody, BAF210 biotinylated anti-human TNFα detect antibody).

Ex vivo/In vivo assessment

The ability of the compounds of this invention as ex vivo TNFαinhibitors were assessed in the rat or mouse. Briefly, groups of maleWistar Alderley Park (AP) rats (180–210 g) were dosed with compound (6rats) or drug vehicle (10 rats) by the appropriate route, for exampleperoral (p.o.), intraperitoneal (i.p.) or subcutaneous (s.c.). Ninetyminutes later rats were sacrificed using a rising concentration of CO₂and bled out via the posterior vena cavae into 5 Units of sodiumheparin/ml blood. Blood samples were immediately placed on ice andcentrifuged at 2000 rpm for 10 min at 4° C. and the harvested plasmasfrozen at −20° C. for subsequent assay of their effect on TNFαproduction by LPS-stimulated human blood. The rat plasma samples werethawed and 175 μl of each sample was added to a set format pattern in a96 well round bottom plate (Corning 25850), 50 μl of heparinized humanblood was then added to each well, mixed and the plate was incubated for30 min at 37° C. (humidified incubator). LPS (25 μl ; finalconcentration 10 μg/ml) was added to the wells and incubation continuedfor a further 5.5 hours. Control wells were incubated with 25 μl ofmedium alone. Plates were then centrifuged for 10 min at 2000 rpm and200 μl of the supernatants were transferred to a 96 well plate andfrozen at −20° C. for subsequent analysis of TNF concentration by ELISA.

Data analysis by dedicated software calculates for each compound/dose:${\%\mspace{20mu}{inhibition}\mspace{14mu}{of}\mspace{14mu}{TNF}\;\alpha} = {\frac{{{Mean}\mspace{14mu}{TNF}\;\alpha\mspace{11mu}({Controls})} - {{Mean}\mspace{14mu}{TNF}\;\alpha\mspace{11mu}({Treated})}}{{Mean}\mspace{14mu}{TNF}\;\alpha\mspace{14mu}({Controls})} \times 100}$

Alternatively, mice could be used instead of rats in the aboveprocedure.

Test as anti-arthritic agent

Activity of a compound as an anti-arthritic agent was tested as follows.Acid soluble native type II collagen was shown by Trentham et al. [1] tobe arthritogenic in rats; it caused polyarthritis when administered inFreunds incomplete adjuvant. This is now known as collagen-inducedarthritis (CIA) and similar conditions can be induced in mice andprimates. Recent studies have shown that anti-TNF monoclonal antibodies[2t and TNF receptor-IgG fusion proteins [3] ameliorate established CIAindicating that TNF plays a key role in the pathophysiology of CIA.Moreover, the remarkable efficacy reported for anti-TNF monoclonalantibodies in recent rheumatoid arthritis clinical trials indicates thatTNF plays a major role in this chronic inflammatory disease. Thus CIA inDBA/1 mice as described in references 2 and 3 is a tertiary model whichcan be used to demonstrate the anti-arthritic activity of a compound.Also see reference 4.

-   -   1. Trentham, D. E. et al., (1977) J. Exp. Med., 146. 857.    -   2. Williams, R. O. et al., (1992) Proc. Natl. Acad. Sci., 89,        9784.    -   3. Williams, R. O. et al., (1995) Immunology, 84, 433.    -   4. Badger, M. B. et al., (1996) The Journal of Pharmacology and        Experimental Therapeutics, 279, 1453–1461.

Although the pharmacological properties of the compounds of the FormulaIa vary with structural change as expected, in general a compound of theFormula Ia gives over 30% inhibition of p38α and/or p38β atconcentrations up to 10 μM. No physiologically unacceptable toxicity wasobserved at the effective dose for compounds tested of the presentinvention.

By way of example:

-   -   (i)        6-[N-(3-dimethylaminopropyl)-N-methylamino]-3-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3,4-dihydroquinazolin-4-one        has an IC₅₀ of approximately 0.2μM against p38α and an IC₅₀ of        approximately 2μM in the Human Whole Blood test;    -   (ii)        6-[N-(3-dimethylaminopropyl)-N-methylamino]-3-[5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3,4-dihydroquinazolin-4-one        has an IC₅₀ of approximately 0.05μM against p38β and an IC₅₀ of        approximately 5μM in the Human Whole Blood test; and    -   (iii)        8-[-(3-dimethylaminopropyl)-N-methylamino]-3-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3,4-dihydroquinazolin-4-one        has an IC₅₀ of approximately 0.1μM against p38α and an IC₅₀ of        approximately 7 μM in the Human Whole Blood test.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises an amide derivative of theFormula Ia or Ib, or a pharmaceutically-acceptable or in-vivo-cleavableester thereof, as defined hereinbefore or an amide derivative selectedfrom 3-(5-benzamido-2-methylphenyl)-2-methyl-3,4dihydroquinazolin-4-one,3-[5-(4-methylbenzamido)-2-methylphenyl]-2-methyl-3,4dihydroquinazolin-4-oneand3-[5-(4-methoxybenzamido)-2-methylphenyl]-2-methyl-3.4dihydroquinazolin-4-onein association with a pharmaceutically-acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 0.5 g of active agent compounded with an appropriate andconvenient amount of excipients which may vary from about 5 to about 98percent by weight of the total composition.

The size of the dose for therapeutic or prophylactic purposes of acompound of the Formula Ia will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine.

In using a compound of the Formula Ia for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.5 mg to 75 mg per kg body weight is received,given if required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range, for example, 0.5 mg to30 mg per kg body weight will generally be used. Similarly. foradministration by inhalation. a dose in the range, for example. 0.5 mgto 25 mg per kg body weight will be used. Oral administration is howeverpreferred, particularly in tablet form. Typically, unit dosage formswill contain about 1 mg to 500 mg of a compound of this invention.

According to a further aspect of the invention there is provided anamide derivative of the Formula Ia, or a pharmaceutically-acceptablesalt or in-vivo-cleavable ester thereof, as defined hereinbefore for usein a method of treatment of the human or animal body by therapy.

According to a further aspect of the invention there is provided the useof an amide derivative of the Formula Ia or Ib, or apharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, asdefined hereinbefore or an amide derivative selected from3-(5-benzamido-2-methylphenyl)-2-methyl-3,4-dihydroquinazolin-4-one,3-[5-(4-methylbenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-oneand3-[5-(4-methoxybenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-onein the manufacture of a medicament for use in the treatment of diseasesor medical conditions mediated by cytokines.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by cytokines which comprisesadministering to a warm-blooded animal an effective amount of an amidederivative of the Formula Ia or Ib, or a pharmaceutically-acceptablesalt or in-vivo-cleavable ester thereof, as defined hereinbefore or ofan amide derivative selected from3-(5-benzamido-2-methylphenyl)-2-methyl-3,4-dihydroquinazolin-4-one,3-[5-(4-methylbenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-oneand3-[5-(4-methoxybenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-one.

In a further aspect the present invention provides the use of an amidederivative of the Formula Ia, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, as defined hereinbefore or an amidederivative selected from3-(5-benzamido-2-methylphenyl)-2-methyl-3,4-dihydroquinazolin-4-one,3-[5-(4-methylbenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-oneand3-[5-(4-methoxybenzmido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-onein the manufacture of a medicament for use in the treatment of diseasesor medical conditions mediated by TNF, IL-I, IL-6 or IL-8.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by TNF, IL-1, IL-6 or IL-8 whichcomprises administering to a warm-blooded animal an effective amount ofan amide derivative of the Formula Ia or Ib, or apharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, asdefined hereinbefore or of an amide derivative selected from3-(5-benzamido-2-methylphenyl)-2-methyl-3,4-dihydroquinazolin-4-one,3-[5-(4-methylbenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-oneand3-[5-(4-methoxybenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-one.

In a further aspect the present invention provides the use of an amidederivative of the Formula Ia, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, as defined hereinbefore or an amidederivative selected from3-(5-benzamido-2-methylphenyl)-2-methyl-3,4-dihydroquinazolin-4-one,-[5-(4-methylbenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-oneand3-[5-(4-methoxybenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-onein the manufacture of a medicament for use in the treatment of diseasesor medical conditions mediated by TNF.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by TNF which comprisesadministering to a warm-blooded animal an effective amount of an amidederivative of the Formula Ia, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, as defined hereinbefore or of an amidederivative selected from3-(5-benzamido-2-methylphenyl)-2-methyl-3,4-dihydroquinazolin-4-one,3-[5-(4-methylbenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-oneand3-[5-(4-methoxybenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-one.

In a further aspect the present invention provides the use of an amidederivative of the Formula Ia, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, or an amide derivative selected from3-(5-benzamido-2-methylphenyl)-2-methyl-3,4-dihydroquinazolin-4-one,3-[5-(4-methylbenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-oneand3-[5-(4-methoxybenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-oneas defined hereinbefore in the manufacture of a medicament for use ininhibiting TNF, IL-1, IL-6 or IL-8.

In a further aspect the present invention provides a method ofinhibiting TNF, IL-1, IL-6 or IL-8 which comprises administering to awarm-blooded animal an effective amount of an amide derivative of theFormula Ia, or a pharmaceutically-acceptable salt or in-vivo-cleavableester thereof, as defined hereinbefore or of an amide derivativeselected from3-(5-benzamido-2-methylphenyl)-2-methyl-3,4-dihydroquinazolin-4-one,3-[5-(4-methylbenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-oneand3-[5-(4-methoxybenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-one.

In a further aspect the present invention provides the use of an amidederivative of the Formula Ia, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, as defined hereinbefore or an amidederivative selected from3-(5-benzamido-2-methylphenyl)-2-methyl-3,4-dihydroquinazolin-4-one,3-[5-(4-methylbenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-oneand3-[5-(4-methoxybenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-onein the manufacture of a medicament for use in inhibiting TNF.

In a further aspect the present invention provides a method ofinhibiting TNF which comprises administering to a warm-blooded animal aneffective amount of an amide derivative of the Formula Ia, or apharmaceutically-acceptable salt or in vivo-cleavable ester thereof, asdefined hereinbefore or of an amide derivative selected from3-(5-benzamido2-methylphenyl)-2-methyl-3,4-dihydroquinazolin-4-one,3-[5-(4-methylbenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-oneand3-[5-(4-methoxybenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-one.

In a further aspect the present invention provides the use of an amidederivative of the Formula Ia, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, as defined hereinbefore or an amidederivative selected from3-(5-benzamido-2-methylphenyl)-2-methyl3,4-dihydroquinazolin-4-one,3-[5-(4-methylbenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-oneand3-[5-(4-methoxybenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-onein the manufacture of a medicament for use in the treatment of diseasesor medical conditions mediated by p38 kinase.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by p38 kinase which comprisesadministering to a warm-blooded animal an effective amount of an amidederivative of the Formula Ia, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, as defined hereinbefore or of an amidederivative selected from3-(5-benzamido-2-methylphenyl)-2-methyl-3,4-dihydroquinazolin-4-one,3-[5-(4-methylbenzamido)-2-methylphenyl]-2-methyl-3.4-dihydroquinazolin-4-oneand 3-[5-(4-methoxybenzamido)-2-methylphenyl]-2-methyl3,4-dihydroquinazolin-4-one.

In a further aspect the present invention provides the use of an amidederivative of the Formula Ia, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, or an amide derivative selected from3-(5-benzamido-2-methylphenyl)-2-methyl-3,4-dihydroquinazolin-4-one,3-[5-(4-methylbenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-one and3-[5-(4-methoxybenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-onein the manufacture of a medicament for use in the production of a p38kinase inhibitory effect.

In a further aspect the present invention provides a method of providinga p38 kinase inhibitory effect which comprises administering to awarm-blooded animal an effective amount of an amide derivative of theFormula Ia, or a pharmaceutically-acceptable salt or in-vivo-cleavableester thereof, as defined hereinbefore or of an amide derivativeselected from3-(5-benzamido-2-methylphenyl)-2-methyl-3,4-dihydroquinazolin-4-one,3-[5-(4-methylbenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-oneand3-[5-(4-methoxybenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-one.

In a further aspect the present invention provides the use of an amidederivative of the Formula Ia, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, as defined hereinbefore or an amidederivative selected from3-(5-benzamido-2-methylphenyl)-2-methyl-3,4-dihydroquinazolin-4-one,3-[5-(4-methylbenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-oneand3-[5-(4-methoxybenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-onein the manufacture of a medicament for use in the treatment ofrheumatoid arthritis, asthma, irritable bowel disease, multiplesclerosis, AIDS, septic shock, ischaemic heart disease or psoriasis.

In a further aspect the present invention provides a method of treatingrheumatoid arthritis, asthma, irritable bowel disease, multiplesclerosis, AIDS, septic shock, ischaemic heart disease or psoriasiswhich comprises administering to a warm-blooded animal an effectiveamount of an amide derivative of the Formula Ia, or apharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, asdefined hereinbefore or of an amide derivative selected from3-(5-benzamido-2-methylphenyl)-2-methyl-3,4-dihydroquinazolin-4-one,3-[5-(4-methylbenzamido)-2-methiylphenyl]-2-methyl-3,4-dihydroquinazolin-4-one and3-[5-(4-methoxybenzamido)-2-methylphenyl]-2-methyl-3,4-dihydroquinazolin-4-one.

The compounds of this invention may be used in combination with otherdrugs and therapies used in the treatment of disease states which wouldbenefit from the inhibition of cytokines, in particular TNF and IL-1.For example, the compounds of the Formula Ia could be used incombination with drugs and therapies used in the treatment of rheumatoidarthritis, asthma, irritable bowel disease, multiple sclerosis, AIDS,septic shock, ischaemic heart disease, psoriasis and the other diseasestates mentioned earlier in this specification.

For example, by virtue of their ability to inhibit cytolkines, thecompounds of the Formula Ia are of value in the treatment of certaininflammatory and non-inflammatory diseases which are currently treatedwith a cyclooxygenase-inhibitory non-steroidal anti-inflammatory drug(NSAID) such as indomethacin, ketorolac, acetylsalicyclic acid,ibuprofen, sulindac, tolmetin and piroxicam. Co-administration of acompound of the Formula I with a NSAID can result in a reduction of thequantity of the latter agent needed to produce a therapeutic effect.Thereby the likelihood of adverse side-effects from the NSAID such asgastrointestinal effects are reduced. Thus according to a furtherfeature of the invention there is provided a pharmaceutical compositionwhich comprises an amide derivative of the Formula Ia, or apharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, inconjunction or admixture with a cyclooxygenase inhibitory non-steroidalanti-inflammatory agent, and a pharmaceutically-acceptable diluent orcarrier.

The compounds of the invention may also be used with anti-inflammatoryagents such as an inhibitor of the enzyme 5-lipoxygenase.

The compounds of the Formula Ia may also be used in the treatment ofconditions such as rheumatoid arthritis in combination withantiarthritic agents such as gold, methotrexate, steroids andpenicillinamine, and in conditions such as osteoarthritis in combinationwith steroids.

The compounds of the present invention may also be administered indegradative diseases, for example osteoarthritis, withchondroprotective, anti-degradative and/or reparative agents such asDiacerhein, hyaluronic acid formulations such as Hyalan, Rumalon,Arteparon and glucosamine salts such as Antril.

The compounds of the Formula Ia may be used in the treatment of asthmain combination with antiasthmatic agents such as bronchodilators andleukotriene antagonists.

If formulated as a fixed dose such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically-active agent within its approved dosagerange. Sequential use is contemplated when a combination formulation isinappropriate.

Although the compounds of the Formula Ia are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the effects ofcytokines. Thus, they are useful as pharmacological standards for use inthe development of new biological tests and in the search for newpharmacological agents.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

-   -   (i) operations were carried out at ambient temperature. i.e. in        the range 17 to 25° C. and under an atmosphere of an inert gas        such as argon unless otherwise stated;    -   (ii) evaporations were carried out by rotary evaporation in        vacuo and work-up procedures were carried out after removal of        residual solids by filtration;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Merck Kieselgel silica(Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silicaobtained from E. Merck, Darmstadt, Germany or high pressure liquidchromatography (HPLC) was performed on C18 reverse phase silica, forexample on a Dynamax C-18 60Å preparative reversed-phase column;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

-   -   (v) in general, the end-products of the Formula Ia have        satisfactory microanalyses and their structures were confirmed        by nuclear magnetic resonance (NMR) and/or mass spectral        techniques; fast-atom bombardment (FAB) mass spectral data were        obtained using a Platform spectrometer and, where appropriate,        either positive ion data or negative ion data were collected;        NMR chemical shift values were measured on the delta scale        [proton magnetic resonance spectra were determined using a        Varian Gemini 2000 spectrometer operating at a field strength of        300 MHz or a Bruker AM250 spectrometer operating at a field        strength of 250 MHz]; the following abbreviations have been        used: s, singlet; d, doublet; t, triplet; m, multiplet; br,        broad;    -   (vi) intermediates were not generally fully characterised and        purity was assessed by thin layer chromatographic, HPLC,        infra-red (IR) and/or NMR analysis;    -   (vii) melting points are uncorrected and were determined using a        Mettler SP62 automatic melting point apparatus or an oil-bath        apparatus; melting points for the end-products of the Formula Ia        were determined after crystallisation from a conventional        organic solvent such as ethanol, methanol, acetone, ether or        hexane, alone or in admixture; and    -   (viii) the following abbreviations have been used:        -   DMF N,N-dimethylformamide        -   DMSO dimethylsulphoxide.

EXAMPLE 13-(5-benzamido-2-chlorophenyl)-7-methoxy-3,4-dihydroquinazolin-4-one

Triethyl orthoformate (0.189 ml) was added to a stirred mixture ofN-(5-benzamido-2-chlorophenyl)-2-amino-4-methoxybenzamide (0.15 g),ethanol (10 ml) and glacial acetic acid (0.022 ml) and the resultantmixture was heated to 70° C. for 16 hours. The mixture was evaporated.The residue was partitioned between methylene chloride and a saturatedaqueous solution of sodium bicarbonate. The organic phase was dried(MgSO₄) and evaporated and the residue was triturated under a mixture ofethyl acetate and diethyl ether. The material so obtained was furtherpurified by column chromatography on an ion exchange column (isolute SCXcolumn from International Sorbent Technology Limited, Hengoed,Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture ofmethanol and a saturated aqueous ammonium hydroxide solution as eluent.There was thus obtained the title compound (0.054 g); NMR Spectrum:(DMSOd₆) 3.92 (s, 3H), 7.12–7.22 (m, 2H), 7.48–7.6 (m, 3H), 7.68 (d,1H), 7.88–8.0 (m, 3H), 8.04–8.12 (m, 2H), 8.28 (m, 1H), 10.06 (s, 1H);Mass Spectrum: M+H⁺ 406 and 408.

The N-(5-benzamido-2-chlorophenyl)-2-amino-4-methoxybenzamide used as astarting material was prepared as follows:

Benzoyl chloride (5.2 ml) was added to a stirred mixture of2,4-diaminochlorobenzene (6.42 g), triethylamine (12.5 ml) and methylenechloride (100 ml) which had been cooled to 0° C. The mixture was allowedto warm to ambient temperature and was stirred for 16 hours. The mixturewas evaporated and the residue was, triturated under a saturated aqueoussodium bicarbonate solution. The resultant solid was isolated, washed inturn with water and isohexane and dried under vacuum at 55° C. There wasthus obtained N-(3-amino-4-chlorophenyl)benzamide as a solid (10.38 g);NMR Spectrum: (DMSOd₆) 5.32 (s, 2H), 6.9 (m, 1H), 7.1 (d, 1H), 7.37 (d,1H), 7.52 (m, 3H), 7.9 (d, 2H), 10.05 (s, 1H).

Oxalyl chloride (0.781 ml) was added dropwise to a stirred mixture of4-methoxy-2-nitrobenzoic acid (1.6 g), DMF (a few drops) and methylenechloride (30 ml) which had been cooled to 0° C. The mixture was allowedto warm to ambient temperature and was stirred for 4 hours. The mixturewas evaporated. The residue was dissolved in methylene chloride (10 ml)and added dropwise to a stirred mixture ofN-(3-amino-4-chlorophenyl)benzamide (2.0 g). triethylamine (2.49 ml) andmethylene chloride (30 ml). The resultant mixture was stirred at ambienttemperature for 16 hours. The precipitate was isolated, washed with 1Naqueous hydrochloric acid solution and with methanol and dried undervacuum at 40° C. There was thus obtainedN-(5-benzamido-2-chlorophenyl)-4-methoxy-2-nitrobenzamide (2.49 g); NMRSpectrum: (DMSOd₆) 3.9 (s, 3H), 7.39 (d, 1H), 7.47–7.62 (m, 5H), 7.72(d, 1H), 7.78 (d, 1H), 7.97 (d, 2H), 8.14 (s, 1H), 10.28 (s, 1H), 10.46(s, 1H); Mass Spectrum: M+H⁺426 and 428.

Iron powder (2.79 g) was added to a stirred suspension of a portion(2.13 g) of the material so obtained in a mixture of ethanol (100 ml),water (20 ml) and acetic acid (4 ml). The mixture was stirred and heatedto reflux for 6 hours. The mixture was cooled to ambient temperature.Water (50 ml) was added and the resultant mixture was basified by theaddition of sodium carbonate. The mixture was filtered and the filtratewas evaporated. The residue was triturated under water. The resultantsolid was isolated and dried under vacuum at 40° C. There was thusobtained the required starting material (0.911 g); NMR Spectrum:(DMSOd₆) 3.72 (s, 3H), 6.09 (d, 1H), 6.27 (s, 1H), 6.62 (s, 2H),7.45–7.61 (m, 4H), 7.66–7.72 (m, 2H), 7.95 (d, 2H), 8.07 (s, 1H), 9.52(s, 1H), 10.37 (s, 1H);. Mass Spectrum: M+H⁺ 396 and 398.

EXAMPLE 23-(5-benzamido-2-chlorophenyl)-7-methoxy-2-methyl-3,4-dihydroquinazolin-4-one

Using an analogous procedure to that described in Example 1, triethylorthoacetate was reacted withN-(5-benzamido-2-chlorophenyl)-2-amino-4-methoxybenzamide. The materialso obtained was purified by column chromatography on an isolute SCX ionexchange column using initially methanol and then a 99:1 mixture ofmethanol and a saturated aqueous ammonium hydroxide solution as eluent.There was thus obtained the title compound in 27% yield; NMR Spectrum:(DMSOd₆) 2.15 (s, 3H), 3.91 (s, 3H), 7.09–7.14 (m, 2H), 7.46–7.6 (m,3H), 7.71 (d, 1H), 7.87–8.06 (m, 5H), 10.57 (s, 1H); Mass Spectrum:M+H⁺420 and 422.

EXAMPLE 3

Using an analogous procedure to that described in Example 1 or Example 2as appropriate, the appropriate 2-aminobenzamide was reacted withtriethyl orthoformate or triethyl orthoacetate to give the compoundsdescribed in Table I:

TABLE I

No. (R¹)_(m) (R²)_(n) R³ Note 1 6-[N-(3-dimethylaminopropyl)-N- 6-methylhydrogen a methylamino] 2 6-[N-(3-dimethylaminopropyl)-N- 6-methylmethyl b methylamino] 3 6-[N-(3-dimethylaminopropyl)-N- hydrogenhydrogen c methylamino] 4 6-[N-(3-dimethylaminopropyl)-N- hydrogenmethyl d methylamino] 5 6-(4-methylpiperazin-1-yl) 6-methyl hydrogen e 66-(4-methylpiperazin-1-yl) 6-methyl methyl f 76-(4-methylpiperazin-1-yl) hydrogen hydrogen g 86-(4-methylpiperazin-1-yl) hydrogen methyl h 98-[N-(3-dimethylaminopropyl)-N- 6-methyl hydrogen i methylamino] 106-[N-(3-methylaminopropyl)-N- 6-methyl hydrogen j methylamino]Notes a) The product gave the following data: NMR Spectrum: (DMSOd₆)1.73–1.83 (m, 2H), 1.88 (s, 3H), 2.23 (s, 6H), 2.26–2.34 (m, 2H),3.07(s, 3H), 3.44–3.55 (m, 6H) 3.67–3.71 (m, 4H), 7.0 (d, 1H), 7.09 (s, 1H),7.19 (d, 1H), 7.31 (d, 1H), 7.43 (s, 1H), 7.54 (s, 1H), 7.66 (d, 1H)7.75(d, 2H), 8.23 (d, 1H), 8.69 (s, 1H); Mass Spectrum: M+H⁺ 556.

TheN-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-2-amino-5-[N-(3-dimethylaminopropyl)-N-mnethylamino]benzamideused as a starting material was prepared as follows:

Triethylamine (31.8 ml) was added to a stirred mixture of4-methyl-3-nitroaniline (15.8 g), 2-chloropyridine-4-carbonyl chloride(20 g) and methylene chloride (1 liter) and the resultant mixture wasstirred at ambient temperature for 16 hours. The precipitate wasisolated, washed with a saturated aqueous sodium bicarbonate solutionand with methylene chloride and dried under vacuum at 40° C. There wasthus obtained 2-chloro-N-(4-methyl-3-nitrophenyl)pyridine-4-carboxamide(10.2 g). The organic filtrate was washed with a saturated aqueoussodium bicarbonate solution, dried (MgSO₄) and evaporated. The residuewas triturated under methylene chloride and the resultant solid wasisolated and dried under vacuum at 40° C. There was thus obtained asecond crop (8.13 g) of2-chloro-N-(4-methyl-3-nitrophenyl)pyridine-4-carboxamide; NMR Spectrum:(DMSOd₆) 2.48 (s, 3H), 7.51 (d, 1H), 7.86 (m, 1H), 7.96 (m, 2H), 8.49(m, 1H), 8.64 (m, 1H), 10.85 (s, 1H); Mass Spectrum: M+H⁺ 292 and 294.

A mixture of the pyridine-4-carboxamide so produced and morpholine (250ml) was stirred and heated to 100° C. for 18 hours. The mixture waspoured into water (250 ml) and stirred for 10 minutes. Methylenechloride (30 ml) was added and the resultant mixture was stirred for 30minutes. The resultant solid was isolated, washed with methylenechloride and dried in a vacuum oven at 40° C. for 18 hours. There wasthus obtainedN-(4-methyl-3-nitrophenyl)-2-morpholinopyridine-4-carboxamide (d 7.34g); NMR Spectrum: (DMSOd₆) 2.48 (s, 3H), 3.52 (m, 4H), 3.71 (m, 4H), 7.1(d, 1H), 7.25 (s, 1H), 7.49 (d, 1H) 7.97 (m, 1H), 8.29 (m, 1H), 8.49 (m,1H), 10.62 (s, 1H); Mass Spectrum: M+H⁺ 343.

A mixture of a portion (8.5 g) of the material so obtained, 5%palladium-on-carbon catalyst (0.85 g) and methanol (600 ml) was stirredunder an atmosphere pressure of hydrogen gas for 18 hours. Methylenechloride (400 ml) was added and the reaction mixture was filteredthrough diatomaceous earth. The filtrate was evaporated to giveN-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide (6.41 g);NMR Spectrum: (DMSOd₆) 2.01 (s, 3H), 3.52 (m, 4H), 3.73 (m, 4H), 4.83(s, 2H), 6.78 (d, 1H), 6.84 (d, 1H) 7.04–7.08 (m, 2H), 7.2 (s, 1H), 8.24(d, 1H), 9.95 (s, 1H); Mass Spectrum: M+H⁺ 313.

Oxalyl chloride (0.55 g) was added dropwise to a stirred mixture of5-chloro-2-nitrobenzoic acid (0.726 g), DMF (a few drops) and methylenechloride (25 ml) which had been cooled to 0° C. The mixture was allowedto warm to ambient temperature and was stirred for 5 hours. The mixturewas evaporated. The residue was dissolved in methylene chloride (10 ml)and was added dropwise to a stirred mixture ofN-(3-amino-4-methylphenyl)2-morpholinopyridine-4-carboxamide (0.933 g),triethylamine (1.12 ml) and methylene chloride (25 ml). The mixture wasstirred at ambient temperature for 16 hours. The resultant precipitatewas isolated, washed in turn with water, methylene chloride and diethylether and dried under vacuum at 40° C. There was thus obtainedN-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-chloro-9-nitrobenzamide(1.12 g) NMR Spectrum: (DMSOd₆) 2.23 (s, 3H), 3.5–3.54 (m, 4H),3.69–3.73 (m, 4H), 7.12 (d, 1H), 7.2–7.25 (m, 2H), 7.58 (d, 1H), 7.81(d, 1H), 7.87–7.9 (m, 21H), 8.15 (d, 1H), 8.26 (d, 1H); Mass Spectrum:M+H⁺ 496 and 498.

A mixture of a portion (0.2 g) of the material so obtained andN-(3-dimethylaminopropyl)-N-methylamine (1.5 ml) was stirred and heatedto 100° C. for 16 hours. The mixture was cooled and poured into water.The resultant precipitate was isolated, washed in turn with water anddiethyl ether and dried under vacuum at 40° C. There was thus obtainedN-[2-methyl-5-(9-morpholinopyrid-4-ylcarbonylamino)phenyl]5-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamide(0.223 g); NMR Spectrum: (DMSOd₆) 1.62–1.74 (m, 2H), 2.12 (s, 6H),2.18–2.26 (m, 5H), 3.08 (s, 3H), 3.50–3.54 (m, 6H), 3.69–3.71 (m, 4H),6.75 (s, 1H), 6.84 (s, 1H), 7.12.(d, 1H), 7.2 (d, 1H), 7.26 (s, 1H),7.68 (d, 1H), 7.9 (s, 1H), 8.04 (d, 1H), 8.26 (d, 1H), 9.82 (s, 1H),10.04 (s, 1H); Mass Spectrum: M+H⁺ 576.

A mixture of the material so obtained, 10% palladium-on-carbon (0.02 g)and methanol (15 ml) was stirred under an atmosphere of hydrogen gas.After cessation of hydrogen uptake, the catalyst was removed byfiltration through diatomaceous earth and the filtrate was evaporated.There was thus obtained the required starting material (0.15 g); MassSpectrum: M+H⁺ 546.

a) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.58–1.7(m, 2H), 1.97 (s, 3H), 2.06 (s, 3H), 2.12 (s, 6H), 2.23 (t, 2H), 2.96(s, 3H), 3.39–3.48 (m, 2H), 3.48–3.52 (m, 4H), 3.68–3.71 (m, 4H), 7.08(d, 1H), 7.15 (s, 1H), 7.22 (s, 1H), 7.32 (m, 1H), 7.42 (d, 1H), 7.51(d, 1H), 7.67 (s, 1H), 7.74 (d, 1H), 8.26 (d, 1H), 10.42 (s, 1H); MassSpectrum: M+H⁺ 570.b) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.66 (m,2H), 2.12 (s, 6H), 2.22 (m, 2H), 2.99 (s, 3H), 3.51 (m, 6H), 3.71 (t,4H), 7.1 (d, 1H), 7.24 (m, 3H), 7.35 (m, 1H), 7.55 (m, 2H), 7.85 (m,2H), 8.05 (s, 1H), 8.27 (d, 1H), 10.51 (broad s, 1H); Mass Spectrum:M+H⁺ 542.

TheN-[3-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-2-amino-5-[N-(3-dimethylaminopropyl)-N-methylamino]benzamideused as a starting material was prepared as follows:

Triethylamine (6.7 ml) was added to a stirred mixture of 3-nitroaniline(3 g), 2-chloropyridine-4-carbonyl chloride (4.6 g) and methylenechloride (50 ml) and the resultant mixture was stirred at ambienttemperature for 40 hours. The mixture was evaporated and the residue wastriturated under water. The solid so obtained was isolated, washed witha saturated aqueous sodium bicarbonate solution and dried under vacuumat 55° C. There was thus obtained2-chloro-N-(3-nitrophenyl)pyridine-4-carboxamide (6.03 g); NMR Spectrum:(DMSOd₆) 7.68 (t, 1H), 7.88 (t, 1H), 7.99 (m, 2H), 8.16 (d, 1H), 8.63(d, 1H), 8.73 (t, 1H), 10.95 (broad s, 1H); Mass Spectrum: M+H⁺ 278.

A mixture of the pyridine-4-carboxamide so produced and morpholine (100ml) was stirred and heated to 130° C. for 3.5 hours and to 150° C. for 2hours. The mixture was poured into water (250 ml) and stirred for 10minutes. The resultant solid was isolated, washed in turn with water andwith isohexane and dried under vacuum at 55° C. There was thus obtainedN-(3 -nitrophenyl)-2-morpholinopyridine-4-carboxamide (6.8 g); NMRSpectrum: (DMSOd₆) 3.52 (t, 4H), 3.71 (t, 4H), 7.12 (d, 1H), 7.25 (s,1H), 7.66 (t, 1H), 7.97 (d, 1H), 8.15 (d, 1H), 8.29 (d, 1H), 8.73 (t,1H), 10.72 (broad s, 1H); Mass Spectrum: M+H⁺ 329.

A mixture of the material so obtained, 10% palladium-on-carbon catalyst(0.68 g), ammonium formate (13 g) and methanol (150 ml) was stirred andheated to reflux for 2 hours. The reaction mixture was filtered throughdiatomaceous earth. The filtrate was evaporated and the residue wastriturated under water. The resultant solid was isolated, washed in turnwith water and with isohexane and dried under vacuum at 55° C. There wasthus obtained N-(3-aminophenyl)-2-morpholinopyridine4-carboxamide (5.38g); NMR Spectrum: (DMSOd₆) 3.51 (t, 4H), 3.71 (t, 4H), 5.07 (broad s,2H), 6.33 (d, 1H), 6.81 (d, 1H), 6.95 (t, 1H), 7.05 (m, 2H), 7.2 (s,1H), 8.24 (d, 1H), 9.96 (broad s, 1H); Mass Spectrum: M+H⁺ 299.

Oxalyl chloride (0.66 ml) was added dropwise to a stirred mixture of5-chloro-2-nitrobenzoic acid (1.22 g), DMF (a few drops) and methylenechloride (20 ml). The mixture was stirred at ambient temperature for 4hours. The mixture was evaporated. The residue was dissolved inmethylene chloride (10 ml) and was added to a stirred mixture ofN-(3-aminophenyl)-2-morpholinopyridine-4-carboxamide (1.5 g),triethylamine (1.75 ml) and methylene chloride (20 ml). The mixture wasstirred at ambient temperature for 16 hours. The mixture was evaporatedand the residue was triturated under water. The solid so obtained wasisolated, washed in turn with 2N aqueous sodium hydroxide solution andwith diethyl ether. The material so obtained was purified on a SCXisolute ion exchange column using initially methanol and then a 99:1mixture of methanol and a saturated aqueous ammonium hydroxide solutionas eluent. There was thus obtainedN-[3-(2-morpholinopyrid4-ylcarbonylamino)phenyl]-5-chloro-2-nitrobenzamide(1.96 g); NMR Spectrum: (DMSOd₆) 3.51 (t, 4H), 3.71 (t, 4H), 7.1 (d,1H), 7.23 (s, 1H), 7.36 (m, 2H), 7.51 (d, 1H), 7.82 (d, 1H), 7.93 (s,1H), 8.18 (m, 2H), 8.26 (d, 1H), 10.37 (broad s, 1H), 10.73 (broad s,1H); Mass Spectrum: M+H⁺ 482.

A mixture of a portion (0.384 g) of the material so obtained andN-(3-dimethylaminopropyl)-N-methylamine (4 ml) was stirred and heated to120° C. for 4 hours. The mixture was cooled and poured into a mixture ofice and water. The resultant precipitate was isolated, washed withisohexane and dried under vacuum at 55° C. There was thus obtainedN-[3-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamide(0.376 g); NMR Spectrum: (DMSOd₆) 1.67 (m, 2H), 2.11 (s, 6H), 2.2 (t,2H), 3.07 (s, 3H),;3.51 (m, 6H), 3.71 (t, 4H), 6.77 (d, 1H), 6.84 (m,1H), 7.1 (d, 1H), 7.24 (s 1H), 7.31 (m, 2H); 7.48 (d, 1H), 8.04 (d, 1H),8.17 (s, 1H), 8.26 (d, 1H), 10.34 (broad s, 1H), 10.42 (broad s, 1H);Mass Spectrum: M+H⁺ 562.

A mixture of the material so obtained, 10% palladium-on-carbon (0.036g), ammonium formate (0.4 g) and methanol (4 ml) was stirred and heatedto reflux for 2 hours The reaction mixture was filtered throughdiatomaceous earth. The filtrate was evaporated and the residue waspurified by column chromatography using C18 reversed phase silica anddecreasingly polar mixtures of water and methanol as eluent. There wasthus obtained the required starting material (0.256 g); NMR Spectrum:(DMSOd₆) 1.59 (m, 2H), 2.14 (s, 6H), 2.26 (t, 2H), 2.77 (s, 3H), 3.18(t, 2H), 3.52 (t, 4H), 3.71 (t, 4H), 6.67 (d, 1H), 6.82 (m, 1H), 6.93(d, 1H), 7.11 (d, 1H), 7.29 (m, 2H), 7.39 (d, 1H), 7.46 (d, 1 H), 8.17(s, 1H), 8.26 (d, 1H), 10.05 (broad s, 1H), 10.31 (broad s, 1H); MassSpectrum: M+H⁺ 532.

c) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.64 (m,2H), 2.11 (s, 9H), 2.21 (m, 2H), 2.96 (s, 3H), 3.43 (t, 2H), 3.51 (m,4H), 3.7 (m, 4H), 7.09 (d, 1H), 7.15 (m, 2H), 7.23 (s, 1H), 7.33 (m,1H), 7.48 (m, 2H), 7.73 (s, 1H), 7.83 (d, 1H), 8.27 (d 1H), 10.49 (broads, 1H); Mass Spectrum: M+H⁺ 556.d) The product gave the following data Mass Spectrum: M+H⁺ 540.

The N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-2-amino-5-(4-methylpiperazin-1-yl)benzamide used as a startingmaterial was prepared as follows:

In an analogous procedure to that described in the fifth paragraph ofthe portion of Note a) which is concerned with the preparation ofstarting materials,N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-chloro-2-nitrobenzamidewas reacted with 1-methylpiperazine to giveN-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-(4-methylpiperazin-1-yl)-2-nitrobenzamide;NMR Spectrum: (DMSOd₆) 2.21 (s, 3H), 2.24 (s, 3H), 2.41–2.47 (m, 4H),2.63–2.69 (m, 2H), 3.46–3.53 (m, 8H), 3.69–3.72 (m, 4H), 7.0 (s, 1H)7.04–7.12 (m, 2H), 7.19 (d, 1H), 7.25 (s, 1H), 7.57 (d, 1H), 7.88 (s,1H), 8.04 (d, 1H), 8.26 (d, 1H), 9.83 (s, 1H), 10.33 (s, 1H); MassSpectrum: M+H⁺ 560.

In an analogous procedure to that described in the sixth paragraph ofthe portion of Note a) which is concerned with the preparation ofstarting materials,N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-(4-methylpiperazine-1-yl)2-nitrobenzamidewas reduced to give the required starting material; Mass Spectrum: M+H⁺530.

e) The product gave the following data: Mass Spectrum: M+H⁺ 554.

f) The product gave the following data: NMR Spectrum: (DMSOd₆) 2.22 (s,3H), 2.4, (m, 4H), 3.3 (m, 4H), 3.51 (t, 4H), 3.71 (t, 4H), 7.1 (d, 1H),7.25 (m, 2H), 7.47 (s, 1H), 7.54 (t, 1H), 7.6 (s, 2H), 7.87 (m, 2H),8.14 (s, 1H), 8.28 (d, 1H), 10.52 (broad s, 1H); Mass Spectrum: M+H⁺526.

TheN-[3-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-2-amino-5-(4-methylpiperazin-1-yl)benzamideused as a starting material was prepared as follows:

In an analogous procedure to that described in the fifth paragraph ofthe portion of Note c) which is concerned with the preparation ofstarting materials,N-[3-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-chloro-2-nitrobenzamidewas reacted with 1-methylpiperazine to giveN-[3-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-(4-methylpiperazin-1-yl)-2-nitrobenzamidein 89% yield; NMR Spectrum: (DMSOd₆) 2.2 (s, 3H), 2.41 (m, 4H) )3.5 (m,8H), 3.71 (t, 4H), 7.07 (m, 3H), 7.31 (m, 3H), 7.48 (d, 1H), 8.03 (d,1H), 8.16 (s, 1H), 8.26 (d, 1H), 10.35 (broad s, 1H), 10.44 (broad s,1H); Mass Spectrum: M+H⁺ 546.

In an analogous procedure to that described in the sixth paragraph ofthe portion of Note c) which is concerned with the preparation ofstarting materials,N-[3-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-(4-methylpiperazin-1-yl)2-nitrobenzamidewas reduced. The material so obtained was purified by columnchromatography on an isolute SCX ion exchange column using initiallymethanol and then a 99:1 mixture of methanol and a saturated aqueousammonium hydroxide solution as eluent. There was thus obtained therequired starting material in 50% yield; NMR Spectrum: (DMSOd₆) 2.2 (s,3‘H) 2.4 (m, 4H), 3.0 (t, 4H), 3.52 (t, 4H), 3.71 (t, 4H), 6.68 (d, 1H),6.96 (d, 1H), 7.1 (m, 2H), 7.25 (m, 2H), 7.4 (m, 2H), 8.15 (s, 1H), 8.26(d, 1H), 10.01 (broad s, 1H), 10.31 (broad s, 1H); Mass Spectrum: M+H⁺516.

g) The product gave the following data: NMR Spectrum: (DMSOd₆) 2.12 (s,3H), 2.21 (s, 3H), 2.5 (m, 4H), 3.22 (m, 4H), 3.51 (m, 4H), 3.7 (m, 4H),7.09 (d, 1H), 7.18 (m, 2H), 7.37 (s, 1H), 7.54 (m, 3H), 7.74 (s, 1H),7.83 (d, 1H), 8.27 (d, 1H), 10.5 (broad s, 1H): Mass Spectrum: M+H⁺ 540.h) The product gave the following data: Mass Spectrum: M+H⁺ 556.

TheN-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-2-amino-3-[N-(3-dimethylaminopropyl)-N-methylamino]benzamideused as a starting material was prepared as follows:

In an analogous procedure to that described in the fourth paragraph ofthe portion of Note a) which is concerned with the preparation ofstarting materials, 3-chloro-2-nitrobenzoyl chloride (obtained by thereaction of 3-chloro-2-nitrobenzoic acid and oxalyl chloride) wasreacted withN-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide to giveN-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3-chloro-2-nitrobenzamide;NMR Spectrum: (DMSOd₆) 2.2 (s, 3H), 3.49–3.53 (m, 4H) 3.69–3.73 (m, 4H),7.1 (d, 1H), 7.18–7.24 (m, 2H), 7.58 (d, 1H), 7.68–7.78 (m, 2H), 7.58(d, 1H), 7.68–7.78 (m, 2H), 7.84–8.0 (m, 2H), 8.25 (d, 1H); MassSpectrum: M+H⁺ 496 and 498.

In an analogous procedure to that described in the fifth paragraph ofthe portion of Note a) which is concerned with the preparation ofstarting materials,N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3-chloro-2-nitrobenzamidewas reacted with N-(3-dimethylaminopropyl)-N-methylamine to giveN-[2-methyl-5-(2-morpholinopyrid4-ylcarbonylamino)phenyl]-3-[N-(3-diethylaminopropyl)-N-methylamino]-2-nitrobenzamide;NMR Spectrum: (DMSOd₆) 1.44–1.58 (m, 2H), 2.06 (s, 6), 2.15 (t, 2H),2.21 (s 3H), 2.69 (s, 3H)3.02 (t, 2H), 3.48–3.53 (m, 4H)-3.69–3.73 (m,4H), 7.1 (d, 1H), 7.19–7.25 (m, 2H), 7.44–7.62 (m, 3H), 7.74–7.64 (m,1H), 7.94 (d, 1H), 8.26 (d, 1H), 10.13 (s, 1H), 10.32 (s, 1H); MassSpectrum: M+H⁺ 576.

In an analogous procedure to that described in the sixth paragraph ofthe portion of Note a) which is concerned with the preparation ofstarting materials,N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamidewas reduced catalytically to give the required starting material; MassSpectrum: M+H⁺ 546.

i) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.6–1.75(m, 2H), 2.05 (s, 3H), 2.28 (s, 3H), 2.47–2.52 (m, 2H), 2.99 (s, 3H),3.49–3.53 (m, 6H), 3.69–3.73 (m, 4H), 7.08 (d, 1H), 7.22 (s, 2H),7.34–7.24 (m, 2H), 7.6 (d, 1H) 7.75–7.8 (m, 2H), 7.97 (s, 1H), 8.28 (d,1H), 10.42 (s, 1H); Mass Spectrum: M+H⁺ 542.

TheN-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-2-amino-5-[N-(3-methylaminopropyl)-N-methylamino]benzamideused as a starting material was prepared as follows:

In an analogous procedure to that described in the fifth paragraph ofthe portion of Note a) which is concerned with the preparation ofstarting materials,N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-chloro-2-nitrobenzamidewas reacted with N-(3-methylaminopropyl)-N-methylamine to giveN-[2-methyl-5-(2-morpholinopyrid4-ylcarbonylamino)phenyl]-5-[N-(3-methylaminopropyl)-N-methylamino]-2-nitrobenzamide:NMR Spectrum: (DMSOd₆) 1.61–1.74 (m, 2H), 2.35 (s, 3H), 2.26 (m, 3H),2.38–2.44 (m, 2H), 3.09 (s, 3H), 3.5–3.55 (m, 6H), 3.7–3.74 (m, 4H),6.78 (s, 1H), 6.84 (d, 1H), 7.14 (d, 1H), 7.21 (d, 1H), 7.27 (s, 1H),7.6 (d, 1H), 7.9 (s, 1H), 8.04 (d, 1H), 8.27 (d, 1H), 9.83 (s, 1H),10.55 (s, 1H); Mass Spectrum: M+H⁺ 562.

In an analogous procedure to that described in the sixth paragraph ofthe portion of Note a) which is concerned with the preparation ofstarting materials,N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3-[-(3-methylaminopropyl)-N-methylamino]-2-nitrobenzamidewas reduced catalytically to give the required starting material; NMRSpectrum: (DMSOd₆) 1.57–1.62 (m, 2H) 2.2 (s, 3H), 2.25 (s, 3H), 2.47–2.5(m, 2H) 2.77 (s, 3H), 3.19–3.23 (m, 2H),3.5–3.54 (m, 4H), 3.69–3.73 (m,4H), 5.6 (s, 2H), 6.68 (d, 1H), 6.82 (d, 1H), 7.04 (s, 1H), 7.1 (d, 1H),7.2–7.23 (m, 2H), 7.54 (d 1H), 7.83 (d, 1H), 8.26 (d, 1H), 9.75 (s, 1H),10.28 (s, 1H); Mass Spectrum: M+H⁺ 532.

EXAMPLE 4 Using an analogous procedure to that described in Example 1,the appropriate 2-aminobenzamide was reacted with triethyl or trimethylorthoformate to give the compounds described in Table II.

TABLE II

No. (R¹)_(m) (R)_(p) Note 1 6-(4-methylpiperazin-1-yl)3-morpholino-5-tri- a fluoromethyl 2 6-[N-(3-dimethylaminopropyl)-3-morpholino-5-tri- b N-methylamino] fluoromethyl 38-[N-(3-dimethylaminopropyl)- 3-morpholino-5-tri- c N-methylamino]fluoromethyl 4 6-methoxy 3-fluoro-5-morpholino dNotesa) Trimethyl orthoformate was used as the reactant and the product gavethe following data: NMR Spectrum: (DMSOd₆) 2.05 (s, 3H), 2.23 (s, 3H),2.5 (m, 4H), 3.3 (m, 8H), 3.76 (t, 4H), 7.44 (m, 3H), 7.72 (m, 6H), 8.1(s, 1H), 10.52 (br s, 1H); Mass Spectrum: M+H⁺ 607.

TheN-[2-methyl-5-(3-morpholino-5-trifluoromethylbenzamido)phenyl]-2-amino-5-(4-methylpiperazin-1-yl)benzamideused as a starting material was prepared as follows:

Ethyl 3-morpholino-5-trifluoromethylbenzoate was prepared from ethyl3-fluoro-5-trifluoromethylbenzoate by the method described by Brown etal., Tetrahedron Lett., 1999, 40, 1219. The material so obtainedcompound gave the following data: NMR Spectrum: (CDCl₆) 1.36 (t, 3H),3.19 (t, 4H), 3.81 (t, 4H) 4.34 (m, 21H) 7.22 (d 1H) 7.72 (d, 1H), 7.76(s, 1H).

A mixture of ethyl 3-morpholino-5-trifluoromethylbenzoate (0.67 g), 1Naqueous sodium hydroxide solution (3.3 ml) and ethanol (6 ml) wasstirred and heated to reflux for 15 minutes and then left to stand for16 hours. The ethanol was evaporated and the residue was dissolved inwater (6 ml). Hydrochloric acid (1 M, 3.3 ml) was added and theresultant solid was isolated, washed with water and dried. There wasthus obtained 3-morpholino-5-trifluoromethylbenzoic acid as a solid(0.464 g); NMR Spectrum: (DMSOd₆) 3.25 (t 4H), 3.73 (t, 4H), 7.4 (s,1H), 7.53 (s, 1H), 7.65 (s, 1H), 13.3 (s, 1H).

A solution of 3-morpholino-5-trifluoromethylbenzoyl chloride (11.43 g;obtained by the reaction of the benzoic acid with oxalyl chloride usinga conventional procedure) in methylene chloride (200 ml) was added to astirred mixture of 4-methyl-3-nitroaniline (5.47 g), triethylamine (10ml) and methylene chloride (200 ml). The resultant mixture was stirredat ambient temperature for 18 hours. The reaction mixture was washedwith water and with a saturated aqueous sodium bicarbonate solution,dried (MgSO₄) and evaporated. The resultant solid was stirred withdiethyl ether (300 ml) for 16 hours. The resultant solid was collected,washed with diethyl ether and dried. There was thus obtainedN-(4-methyl3-nitrophenyl)-3-morpholino-5-fluorobenzamide as a solid(10.4 g); NMR Spectrum: (CDCl₃) 2.58 (s, 3H), 3.22 (t, 4H), 3.83 (t,4H), 7.21 (s, 2H), 7.32 (d, 1H), 7.41 (s, 1H), 7.58 (s, 1H),7.82 (m,1H), 8.02 (s, 1H), 8.23 (d, 1H).

The compound so obtained was dissolved in ethyl acetate (500 ml) andhydrogenated over 10% palladium-on-carbon catalyst (1. 1 g) under 3atmospheres pressure of hydrogen until the uptake of hydrogen ceased.The catalyst was removed by filtration and the filtrate was evaporated.The residue was triturated under ethyl acetate to giveN-(3-amino-4-methylphenyl)-3-morpholino-5-trifluoromethylbenzamide (8.1g); NMR Spectrum: (CDCl₃) 2.01 (s, 3H), 3.23 (t, 4H), 3.75 (t, 4H), 4.81(s, 2H), 6.77 (m, 1H), 6.83 (d, 1H), 7.02 (d, 1H), 7.25 (s, 1H), 7.58(s, 1H), 7.63 (s, 1H), 9.9 (s, 1H).

Diisopropylethylamine (0.918 ml) was added to a mixture ofN-(3-amino-4-methylphenyl)-3-morpholino-5-trifluoromethylbenzamide (1g),5-chloro-2-nitrobenzoic acid (0.584 g),2-(7-azabenzotriazol-1-yl)-1,1,3.3-tetramethyluroniumhexafluorophosphate(V) (1.2 g) and DMF (6 ml) and the reaction mixturewas stirred at ambient temperature for 16 hours. The mixture was pouredonto a mixture of ice and water and the resultant precipitate wasisolated, washed in turn with methanol and isohexane and dried undervacuum at 55° C. There was thus obtainedN-[2-methyl-5-(3-morpholino-5-trifluoromethylbenzamido)phenyl]-5-chloro-2-nitrobenzamide(0.965 g); NMR Spectrum: (DMSOd₆) 2.24 (s, 3H), 3.3 (m, 4H), 3.76 (m,4H), 7.23 (d, 1H), 7.36 (s, 1H), 7.6 (d, 1H), 7.65 (s, 1H), 7.72 (s,1H), 7.82 (d, 1H), 7.90 (m, 2H), 8.17 (d, 1H), 10.17 (s, 1H), 10.38 (s,1H); Mass Spectrum: M+H⁺ 563.

A mixture of a portion (0.45 g) of the material so obtained andN-methylpiperazine (2 ml) was stirred and heated to 120° C. for 16hours. The reaction mixture was poured onto a mixture of ice and water.The resultant solid was isolated, washed with water and dried undervacuum at 55° C. The solid so obtained was purified by chromatography onan ion exchange column (isolute SCX column) using initially methanol andthen a mixture of methanol and a 1% aqueous ammonium hydroxide solutionas eluent. There was thus obtainedN-[2-methyl-5-(3-morpholino-5-trifluoromethylbenzamido)phenyl]-5-(4-methylpiperazin-1-yl)2-nitrobenzamide(0.29 g); NMR Snectrum: (DMSOd₆) 2.21 (s, 3H), 2.24 (s, 3H), 2.5–3.3 (m,8H), 3.48 (m, 4H), 3.76 (m, 4H), 7.0 (d, 1H), 7.07 (d, 1H), 7.2 (d, 1H),7.36 (s, 1H), 7.6 (m, 3H), 7.88 (s, 1H), 8.04 (d, 1H), 9.84 (s, 1H),10.37 (s, 1H); Mass Spectrum: M+H⁺ 627.

A mixture of the material so obtained, ammonium formate (0.146 g), 10%palladium-on-carbon catalyst (0.029 g) and methanol (5 ml) was stirredand heated to 65° C. for 2 hours. The resultant mixture was filtered andthe filtrate was evaporated. The residue was triturated under methylenechloride and filtered. The filtrate was evaporated to giveN-[2-methyl-5-(3-morpholino-5-trifluoromethylbenzamido)phenyl]-2-amino-5-(4-methylpiperazin-1-yl)benzamidewhich was used without further purification.

b) Trimethyl orthoformate was used as the reactant and the product gavethe following data: NMR Spectrum: (DMSOd₆) 1.67 (m, 2H), 2.05 (s, 3H),2.13 (s, 6H), 2.27 (m, 2H), 3.0 (s, 1H), 3.3 (m, 4H), 3.47 (m, 2H), 3.76(br s, 4H), 7.25 (d, 1H), 7.39 (m, 3H), 7.62 (m, 3H), 7.73 (d, 1H), 7.81(d, 1H), 8.0 (s, 1H), 10.51 (br s, 1H); Mass Siectrum: M+H⁺ 623.

TheN-[2-methyl-5-(3-morpholino-5-trifluoromethylbenzamido)phenyl]-2-amino-5-[N-(3-dimethylaminopropyl)-N-methylamino]benzamideused as a starting material was prepared as follows

A mixture ofN-[2-methyl-5-(3-morpholino-5-trifluoromethylbenzamido)phenyl]-5-chloro-2-nitrobenzamide(0.45 g), N-(3-dimethylaminopropyl)-N-methylamine (2 ml) and DMSO (1 ml)was stirred and heated to 120° C. for 16 hours. The reaction mixture waspoured onto a mixture of ice and water. The resultant solid wasisolated, washed with water and dried under vacuum at 55° C. There wasthus obtainedN-[2-methyl-5-(3-morpholino-5-trifluoromethylbenzamido)phenyl]-5-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamide(0.51 g); NMR Spectrum: (DMSOd₆) 1.69 (m, 2H), 2.12 (s, 6H), 2.24 (m,5H), 3.08 (s, 3H), 3.3 (m, 4H), 3.52 (t, 2H), 3.76 (m, 4H), 6.76 (s,1H), 6.83 (d, 1H), 7.2 (d, 1H), 7.36 (s, 1H), 7.66 (m, 3H), 7.89 (s,1H), 8.04 (d, 1H), 9.82 (s, 1H), 10.37 (s, 1H).

A mixture of the material so obtained, ammonium formate (0.24 g), 10%palladium-on-carbon catalyst (0.05 g) and methanol (10 ml) was stirredand heated to 65° C. for 7 hours. The resultant mixture was filtered andthe filtrate was evaporated. The residue was triturated under methylenechloride and filtered. The filtrate was evaporated to giveN-[2-methyl-5-(3-morpholino-5-trifluoromethylbenzamido)phenyl]-2-amino-5-[N-(3-dimethylaminopropyl)-N-methylamino]benzamidewhich was used without further purification.

c) Trimethyl orthoformate was used as the reactant and the product gavethe following data: NMR Spectrum: (DMSOd₆) 1.72 (m, 2H), 2.06 (m, 9H),2.19 (t, 2H), 2.94 (s, 3H), 3(m, 4H), 3.49 (t, 2H), 3.76 (br s, 4H),7.26 (d, 1H), 7.42 (m, 3H), 7.68 (m, 3H), 7.8 (m, 2H), 8.21 (s, 1H),10.49 (br s, 1H); Mass Spectrum: M+H⁺ 623.

TheN-[2-methyl-5-(3-morpholino-5-trifluoromethylbenzamido)phenyl]-2-amino-3-N-(3-dimethylaminopropyl)-N-methylamino]benzamideused as a starting material was prepared as follows:

Diisopropylethylamine (0.46 ml) was added to a mixture ofN-(3-amino-4-methylphenyl)-3-morpholino-5-trifluoromethylbenzamide (0.5g), 3-chloro-2-nitrobenzoic acid (0.292 g),2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate(V) (0.6 g) and DMF (3 ml) and the reaction mixturewas stirred at ambient temperature for 16 hours. The mixture was pouredonto a mixture of ice and water and the resultant precipitate wasisolated, washed in turn with methanol and isohexane and dried undervacuum at 55° C. There was thus obtainedN-[2-methyl-5-(3-morpholino-5-trifluoromethylbenzamido)phenyl]-3-chloro-2-nitrobenzamide(0.45 g); NMR Spectrum: (DMSOd₆) 2.22 (s, 3H), 3.3 (m, 4H), 3.76 (m,4H), 7.25 (d, 1H), 7.37 (s, 1H), 7.71 (m, 5H), 7.96 (d, 2H), 10.36 (brs, 1H), 10.38 (br s, 1H); Mass Spectrum: M+H⁺ 563.

A mixture of the material so obtained,N-(3-dimethylaminopropyl)-N-methylamine (2 ml) and DMSO (1 ml) wasstirred and heated to 120° C. for 16 hours. The reaction mixture waspoured onto a mixture of ice and water. The resultant solid wasisolated, washed with water and dried under vacuum at 55° C. There wasthus obtainedN-[2-methyl-5-(3-morpholino-5-trifluoromethylbenzamido)phenyl]-3-[-(3-dimethylaminopropyl)N-methylamino]-2-nitrobenzamide (0.51 g); NMR Spectrum: (DMSOd₆) 1.52(m, 2H), 2.06 (s, 6H), 2.15 (m, 2H), 2.22 (s, 3H), 2.69 (s, 3H), 3.03(t, 2H), 3.3 (m, 4H), 3.76 (m, 4H), 7.22 (d, 1H), 7.36 (m, 2H), 7.53 (m,4H), 7.73 (d, 2H), 10.14 (br s, 1H), 10.35 (br s, 1H).

A mixture of the material so obtained, ammonium formate (0.24 g), 10%palladium-on-carbon catalyst (0.05 g) and methanol (10 ml) was stirredand heated to 65° C. for 7 hours. The resultant mixture was filtered andthe filtrate was evaporated. The residue was triturated under methylenechloride and filtered. The filtrate was evaporated to giveN-[2-methyl-5-(3-morpholino-5-trifluoromethylbenzamido)phenyl]-2-amino-3-[N-(3-dimethylaminopropyl)-N-methylamino]benzamidewhich was used without further purification.

d) Trimethyl orthoformate was used as the reactant and the product gavethe following, data: NMR Spectrum: (DMSOd₆) 2.06 (s, 3H), 3.21 (m, 4H),3.73 (m, 4H), 3.89 (s, 3H), 6.97 (d, 1H), 7.11 (d, 1H), 7.29 (s, 1H),7.42 (d, 1H), 7.49 (d, 1H), 7.58 (d, 1H), 7.72 (d, 1H), 7.78 (m, 2H),8.17 (s, 1H), 10.33 (s, 1H); Mass Spectrum: M+H⁺ 489.

TheN-[2-methyl-5-(3-fluoro-5-morpholinobenzamido)phenyl]-2-amino-5-methoxybenzamideused as a starting material was prepared as follows:

A solution of 3,5-difluorobenzoyl chloride (2.82 g) in methylenechloride (20 ml) was added to a stirred mixture of4-methyl-3-nitroaniline (2.28 g), triethylamine (4.35 ml) and methylenechloride (80 ml). The resultant mixture was stirred at ambienttemperature for 16 hours. The precipitate was isolated, washed withmethylene chloride and dried. There was thus obtainedN-(4-methyl-3-nitrophenyl)-3,5-difluorobenzamide; NMR Spectrum: (DMSOd₆)2.43 (s, 3H), 7.43 (m, 2 H), 7.63 (m, 2 H) 7.95 (m, 2H), 8.43 (d, 1H),10.42 (s 1H); Mass Spectrum: M+H⁺ 293.

A mixture of a portion (1 g) of the material so obtained and morpholine(5 ml) was stirred and heated to 1 00° C. for 48 hours and then to 120°C. for 24 hours. The reaction mixture was cooled and poured into water(100 ml). The resultant solid was isolated, washed with water and dried.The material so obtained was purified by column chromatography on silicausing a 1:1 mixture of isohexane and ethyl acetate as eluent. There wasthus obtained N-(4-methyl-3-nitrophenyl)-3-fluoro-5-morpholinobenzamideas a solid (0.53 g). NMR Spectrum: (DMSOd₆) 2.46 (s, 3H), 3.22 (t, 4H),3.75 (t, 4H), 6.98 (m, 1H), 7.12 (d, 1H), 7.27 (s, 1H), 7.46 (d, 1H),7.96 (m, 1H), 8.43 (d, 1H), 10.48 (s, 1H); Mass Spectrum: M+H⁺ 360.

A portion (0.483 g) of the compound so obtained was dissolved in ethylacetate (40 ml) and hydrogenated over 10% palladium-on-carbon catalyst(0.6 g) under an atmosphere of hydrogen until the uptake of hydrogenceased. The catalyst was removed by filtration and the filtrate wasevaporated. The residue was triturated under diethyl ether (25 ml). Theresultant solid was collected, washed with diethyl ether and dried.There was thus obtainedN-(3-amino-4-methylphenyl)-3-fluoro-5-morpholinobenzamide (0.341 g); NMRSpectrum: (DMSOd₆) 1.99 (s, 3H), 3.19 (t, 4H), 3.76 (t, 4H), 4.8 (s,2H), 6.75 (d, 1H), 6.82 (d, 1H), 6.9 (d, 1H), 7.02 (s, 1H), 7.04 (d,1H), 7.23 (s, 1H), 9.81 (s, 1H).

Oxalyl chloride (0.523 ml) was added to a stirred mixture of5-methoxy-2-nitrobenzoic acid (0.99 g), DMF (a few drops) and methylenechloride (30 ml) and the mixture was stirred at ambient temperature for3.5 hours. The mixture was evaporated and the residue was dissolved inmethylene chloride (30 ml) andN-(3-amino-4-methylphenyl)3-fluoro-5-morpholinobenzamide (1.65 g) andtriethylamine (0.697 ml) were added in turn.

The resultant mixture was stirred at ambient temperature for 2 hours.The mixture was evaporated and the residue was triturated under water.The resultant solid was isolated, washed in turn with a saturatedaqueous sodium bicarbonate solution, water and diethyl ether and driedunder vacuum at 55° C. There was thus obtainedN-[2-methyl-5-(3-fluoro-5-morpholinobenzamido)phenyl]-5-methoxy-2-nitrobenzamide(2.29 g); NMR Spectrum: (DMSOd₆) 2.24 (s, 3H), 3.23 (m, 4H), 3.75 (m,4H), 3.95 (s, 3H), 6.96 (d, 1H), 7.17 (m, 4H), 30 7.32 (s, 1H), 7.58 (d,1H), 7.89 (s, 1H), 8.18 (d, 1H), 10.0 (s, 1H), 10.22 (s, 1H); MassSpectrum: M+H⁺ 509.

A mixture of a portion (1.28 g) of the material so obtained, 10%palladium-on-carbon catalyst (0.128 g) and methanol (60 ml) was stirredunder an atmosphere of hydrogen gas for 20 hours. Ethyl acetate (30 ml)was added and the reaction mixture was stirred for an additional 2 hoursunder a hydrogen atmosphere. The reaction mixture was filtered and thefiltrate was evaporated. The residue was dissolved in the minimum amountof ethyl acetate and a solid was precipitated by the addition of diethylether. The solid was isolated and dried under vacuum at 55° C. There wasthus obtainedN-[2-methyl-5-(3-fluoro-5-morpholinobenzamido)phenyl]-2-amino-5-methoxybenzamide(0.98 g); NMR Spectrum: (DMSOd₆) 2.2 (s, 3H), 3.22 (m, 4H), 3.74 (m,7H), 5.93 (br s, 2H), 6.72 (d, 1H), 6.92 (m, 2H), 7.12 (d, 1H), 7.22 (d,1H), 7.27 (m, 2H), 7.54 (d, 1H), 7.77 (s, 1H), 9.69 (s, 1H), 10.14 (s,1H)-Mass Spectrum: M+H⁺ 479.

EXAMPLE 53–15-(2-Chloropyrid-4-ylcarbonylamino)-2-methylphenyl]-6-(4-methylpiperazin-1-yl)3,4-dihydroquinazolin-4-one

2-Chloropyridine-4-carbonyl chloride (0.61 g) was added to a stirredmixture of3-(5-amino-2-methylphenyl)-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one(1 g), triethylamine (1 g) and methylene chloride (15 ml) and theresultant mixture was stirred at ambient temperature for 18 hours. Themixture was washed with a saturated aqueous sodium bicarbonate solutionand the organic phase was evaporated. There was thus obtained the titlecompound (1.28 g); NMR Spectrum: (DMSOd₆) 2.05 (s, 3H), 2.22 (s, 3H),2.46–2.5 (m, 4H), 3.25–3.28 (m, 4H), 7.42–7.47 (m, 2H), 7.62 (s, 1H),7.76–7.79 (m, 2H), 7.85 (d, 1H), 7.98 (s, 1H), 8.07 (s, 1H), 8.61 (d,1H), 10.65 (s, 1H); Mass Spectrum: M+H⁺ 489 & 491.

The3-(5-amino-2-methylphenyl)-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-oneused as a starting material was prepared as follows:

Oxalyl chloride (8.5 ml) was added dropwise to a stirred solution of5-chloro-2-nitrobenzoic acid (15.1 g) in a mixture of methylene chloride(200 ml) and DMF (a few drops) which had been cooled to 0° C. Themixture was allowed to warm to ambient temperature and was stirred for afurther 4 hours. The solvent was evaporated. The residue was dissolvedin methylene chloride (300 ml) and added dropwise to a stirred mixtureof 2-methyl-5-nitroaniline (10.6 g), triethylamine (27.2 ml) andmethylene chloride (300 ml). The resultant mixture was stirred atambient temperature for 16 hours. The precipitate was isolated, washedin turn with water and diethyl ether and dried under vacuum at 40° C.There was thus obtainedN-(2-methyl-5-nitrophenyl)-5-chloro-2-nitrobenzamide (24.9 g); NMRSpectrum: (DMSOd₆) 2.34 (s, 3H), 7.46 (d, 1H), 7.75 (s, 1H), 7.88 (d,1H), 8.03–8.16 (m, 2H), 5 8.56 (s, 1H); Mass Spectrum: M+H⁺ 335.

A mixture of a portion (15 g) of the material so obtained andN-methylpiperazine (24.8 ml) was stirred and heated to 100IC for 16hours. The reaction mixture was cooled to ambient temperature and pouredinto water. The resultant precipitate was isolated, washed with waterand dried under vacuum at 40° C. There was thus obtainedN-(2-methyl-5-nitrophenyl)-5-(4-methylpiperazin-1-yl)-2-nitrobenzamide(14.8 g); NMR Spectrum: (DMSOd₆) 2.22 (s, 31), 38 (s, 3H), 2.41–2.45 (m,4H), 3.48–3.53 (m, 4H), 7.08 (d, 1H), 7.17 (s, 1H), 7.53 (d, 1H), 7.98(d, 1H), 8.07 (d, 1H), 8.53 (s, 1H), 10.15 (s, 1H); Mass Spectrum: M+H⁺400.

A mixture of the material so obtained, 10% palladium-on-carbon catalyst(1.48 g) and methanol (500 ml) was stirred under an atmosphere ofhydrogen gas until hydrogen uptake ceased. The catalyst was filtered offand the filtrate was evaporated. There was thus obtainedN-(5-amino-2-methylphenyl)-2-amino-5-(4-methylpiperazin-1-yl)benzamide(10.11 g); NMR Spectrum: (DMSOd₆) 2.02 (s, 3H), 2.2 (s, 3H), 2.4–2.45(m, 4H), 2.97–3.0 (m, 4H), 4.84 (s, 2H), 5.82 (s, 2H), 6.36 (d, 1H),6.57 (s, 1H), 6.66 (d, 1H), 6.85 (d, 1H), 6.92 (d, 1H), 7.18 (s, 20 1H),9.4 (s, 1H); Mass Spectrum: M+H⁺ 340.

A mixture of a portion (8.27 g) of the material so obtained, triethylorthoformate (8.27 ml), glacial acetic acid (0.7 ml) and ethanol (150ml) was stirred and heated to 70° C. for 16 hours. A 1N aqueoushydrochloric acid solution (24 ml) was added and the mixture was stirredat 60° C. for 1 hour. The resultant mixture was evaporated. The residuewas dissolved in water, basified by the addition of sodium bicarbonateand extracted with methylene chloride. The organic extract wasevaporated to give3-(5-amino-2-methylphenyl)6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one(8.29 g); NMR Spectrum: (DMSOd₆) 1.86 (s, 3H), 2.22 (s, 3H), 2.42–2.45(m, 4H), 3.24–3.28 (m, 4H), 5.14 (s, 2H), 6.47 (s, 1H), 6.61 (d, 1H),7.02 (d, 1H), 7.45 (s, 1H), 7.59 (s, 1H), 7.96 (s, 1H); Mass Spectrum:30 M+H⁺ 350.

EXAMPLE 6 3-82-Methyl-5-(2-pyrrolidin-1-ylpyrid-4-ylcarbonylamino)phenyl]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one

A mixture of 3-[5-(2-chloropyrid-4-ylcarbonylamino)-2-methylphenyl]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one(0.18 g) and pyrrolidine (2 ml) was stirred and heated to 100° C. for 16hours. The mixture was cooled to ambient temperature and poured intowater. The resultant solid was isolated, washed with water and driedunder vacuum at 40° C. There was thus obtained the title compound (0.11g); NMR Spectrum: (DMSOd₆) 1.94–1.97 (m, 4H), 2.04 (s, 3H), 2.22 (s,3H), 2.45–2.49 (m, 4H), 3.25–3.28 (m, 4H), 3.4–3.45 (m, 4H), 6.85 (s,1H), 6.96 (d, 1H), 7.42 (d, 1H), 7.42 (d, 1H), 7.44 (s, 1H), 7.62 (s,2H), 7.77–7.79 (m, 2H), 8.07 (s, 1H), 8.2 (s, 1H), 10.42 (s, 1H); MassSpectrum: M+H⁺ 524.

EXAMPLE 7

Using an analogous procedure to that described in Example 6, theappropriate 6-substituted3-[5-(2-chloropyrid-4-ylcarbonylamino)-2-methylphenyl]-3,4-dihydroquinazolin-4-onewas reacted with the appropriate amine to give the compounds describedin Table III.

TABLE III

No. (R¹)_(m) R Note 1 6-(4-methylpiperazin-1-yl) piperidino a 26-(4-methylpiperazin-1-yl) 3-pyrrolin-1-yl b 36-(4-methylpiperazin-1-yl) homopiperidin-1-yl c 46-(4-methylpiperazin-1-yl) azetidin-1-yl d 56-(4-methylhomopiperazin-1-yl) piperidino e 66-(4-methylhomopiperazin-1-yl) pyrrolidin-1-yl f 76-(4-methylhomopiperazin-1-yl) morpholino gNotesa) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.5–1.64(m, 6H), 2.04 (s, 3H), 2.2 (s, 3H), 2.45–2.49 (m, 4H), 3.26–3.29 (m,4H), 3.55–3.59 (m, 4H), 6.98 (d, 1H), 7.19 (s, 1H), 7.42 (d, 1H), 7.47(s, 1H), 7.62 (s, 21H), 7.76–7.78 (m, 2H), 8.07 (s, 1H), 8.21 (s, 1H),10.42 (s, 1H); Mass Snectrum: M+H⁺ 538.b) The product gave the following data: NMR Spectrum: (DMSOd₆) 2.04 (s,3H), 2.22 (s 3H), 2.47–2.5 (m, 4H), 3.25–3.31 (m, 4H), 4.23 (s, 4H),6.03 (s, 2H), 6.87 (s, 1H), 7.01 (d, 1 H), 7.42 (d, 1H), 7.47 (s, 2H),7.62 (d, 2H), 7.76–7.81 (m, 2H), 8.07 (s, 1H), 8.23 (d, 1H), 10.45 (s,1H); Mass Spectrum: M+H⁺ 522.c) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.45–1.47(m, 4H), 1.54–1.56 (m, 4H), 2.04 (s, 3H), 2.22 (s, 3H), 2.45–2.5 (m,4H), 3.25–3.27 (m, 4H), 3.62–3.64 (m, 4H), 6.91 (d, 1H), 6.96 (s, 1H),7.02 (d, 1H), 7.42 (d, 1H), 7.47 (s, 1H), 7.62 (s, 2H), 7.76–7.81 (m,2H), 8.07 (s, 1H), 8.18 (d, 1H), 10.42 (s, 1H); Mass Spectrum: M+H⁺ 552.d) The product gave the following data: Mass Spectrum: M+H⁺ 510.e) The product gave the following data: NMR Snectrum: (CDCl₃) 1.42–1.46(m, 6H), 1.78 (s, 3H), 1.92–2.04 (m, 2H), 2.48 (s, 3H), 2.48–2.56 (m,2H), 2.64–2.72 (m, 2H), 3.44–3.58 (m, 6H), 3.6–3.64 (m, 2H), 6.78 (d,1H), 7.01 (s, 1H), 7.15–7.2 (m, 2H), 7.38 (s, .1 H), 7.5 (s, 1H),7.58–7.68 (m, 3H), 8.12 (d, 1H), 8.4 (s, 1H); Mass Spectrum: M+H⁺ 510.f) The product gave the following data: NMR Spectrum: (CDCl₃) 1.84–2.04(m, 9H), 2.32 (s, 3H), 2.48–2.58 (m, 2H), 2.64–2.7 (m, 2H), 3.32–3.44(m, 4H), 3.5–3.58 (m, 2H), 3.6–3.64 (m, 2H), 6.72–6.79 (m, 2H), 7.14–7.2(m, 2H), 7.38 (s, 1H), 7.52–7.62 (m, 3H), 7.64 (s, 1H), 8.12 (d, 1H),8.44 (s, 1H); Mass Spectrum: M+H⁺ 538.g) The product gave the following data: NMR Spectrum: (CDCl₃) 1.98 (s,3H), 2.02–2.12 (m, 2H), 2.39 (s, 3H), 2.58–2.62 (m, 2H), 2.74–2.8 (m,2H), 3.5–3.58 (m, 4H), 3.6–3.66 (m, 2H), 3.66–3.78 (m, 6H), 6.98 (d,1H), 7.08 (s, 1H), 7.2–7.26 (m, 2H), 7.44 (s, 1H), 7.58 (s, 1H), 7.64(d, 1H), 7.72–7.78 (m, 2H), 8.24 (d, 1H), 8.44 (s, 1H); Mass Snectrum:M+H⁺ 554.

EXAMPLE 83–15-(3,5-Difluorobenzamido)-2-methylphenyl-6-(4-methylpiperazin-1)3,4-dihydroquinazolin-4-one

3,5-Difluorobenzoyl chloride (0.91 g) was added to a stirred mixture of3-(5-amino-2-methylphenyl)-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one(1.5 g), triethylamine (1.04 g) and methylene chloride (50 ml) and theresultant mixture was stirred at ambient temperature for 18 hours. Themixture was washed with a saturated aqueous sodium bicarbonate solutionand the organic phase was evaporated. There was thus obtained the titlecompound (2.04 g); NMR Spectrum: (DMSOd₆) 2.05 (s, 3‘H), 2.22 (s, 3‘H),2.45–2.5 (m, 4H), 3.24–3.3 (m, 4H), 7.41–7.56 (m, 3‘H), 7.61–7.68 (m,4H), 7.75–7.79 (m, 2H), 8.06 (s, 1H), 10.5 (s, 1H); Mass Spectrum: M+H⁺490.

EXAMPLE 9

Using an analogous procedure to that described in Example 6,3-[5-(3,5-difluorobenzamido)-2-methylphenyl]-6-(4-methylpiperazin-1-yl)3,4-dihydroquinazolin-4-one,3-[5-(3-fluoro-4-trifluoromethylbenzamido)-2-methylphenyl]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-oneor3-[5-(3,5-difluorobenzamido)-2-methylphenyl]-6-(4-methylhomopiperazin-12-yl)-3,4-dihydroquinazolin-4-oneas appropriate was reacted with the appropriate amine to give thecompounds described in Table IV.

TABLE IV

No. (R¹)_(m) (R)_(p) Note 1 6-(4-methylpiperazin-1-yl)3-fluoro-5-pyrrolidin-1-yl a 2 6-(4-methylpiperazin-1-yl)3-fluoro-5-piperidino b 3 6-(4-methylpiperazin-1-yl)3-azetidin-1-yl-5-fluoro c 4 6-(4-methylpiperazin-1-yl) 3-fluoro-5-(3- dpyrrolin-1-yl) 5 6-(4-methylpiperazin-1-yl) 3-fluoro-3-morpholino e 66-(4-methylpiperazin-1-yl) 3-morpholino-5-tri- f fluoromethyl 76-(4-methylhomopiperazin-1-yl) 3-fluoro-5-pyrrolidin-1-yl g 86-(4-methylhomopiperazin-1-yl) 3-fluoro-5-piperidino hNotesa) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.95–2.0(m, 4H), 2.04 (s, 3H), 2.18 (s, 3H), 2.0–2.23 (m, 4H), 2.47–2.5 (m, 4H),3.25–3.3 (m, 4H), 6.84–6.89 (m, 2H), 7.22 (d, 1H), 7.4 (d, 1H), 7.47 (s,1H) 7.6–7.62 (m, 2H), 7.76–7.82 (m, 2H), 8.07 (s, 1H). 10.27 (s, 1H);Mass Spectrum: M+H⁺ 541.b) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.22–1.58(m, 6H), 2.04 (s, 3H), 2.2 (s, 3H), 2.45–2.5 (m, 4H), 3.25–3.29 (m, 4H),6.91 (d, 1H), 7.02 (d, 1H), 7.26 (s, 1H), 7.4 (d, 1H), 7.47 (s, 1H),7.62 (s, 2H), 7.76–7.81 (m, 2H), 8.06 (s, 1H), 10.3 (s, 1H); MassSpectrum: M+H⁺ 555.c) The product gave the following data: Mass Spectrum: M+H⁺ 527.d) The product gave the following data: Mass Spectrum: M+H⁺ 539.e) The product gave the following data: Mass Spectrum: M+H⁺ 557.f)3-[5-(3-Fluoro-4-trifluoromethylbenzamido)-2-methylphenyl]-6-(4-methylpiperazinyl)-3,4-dihydroquinazolin-4-oneand morpholine were heated together at 130° C. for 4 days. The productgave the following data: NMR Spectrum: (DMSOd₆) 2.05 (s, 3H), 2.22 (s,3H), 2.4–2.6 (m, 4H), 2.86–2.96 (m, 4H), 3.22–3.32 (m, 4H), 3.64–3.74(m, 4H), 7.4–7.48 (m, 2H), 7.62 (s, 21H), 7.76–7.86 (m, 4H), 8.06 (d,2H), 10.53 (s, 1H); Mass Spectrum: M+H⁺ 607.g)3-[5-(3,5-Difluorobenzamido)-2-methylphenyl]-6-(4-methylhomopiperazin-1-yl)3,4-dihydroquinazolin-4-oneand pyrrolidine were heated together at 95° C. for 16 hours and at 105°C. for 4 hours. The product gave the following data: NMR Spectrum:(CDCl₃) 1.98–2.1 (m, 9H), 2.19 (s, 3H), 2.58–2.62 (m, 2H), 2.72–2.8 (m,2H), 3.24–3.32 (m, 4H), 3.58–3.62 (m, 2H), 3.68–3.72 (m, 2H), 6.32 (d,1H), 6.76 (d, 1H), 6.82 (s, 1H), 7.2–7.3 (m, 2H), 7.44 (s, 1H), 7.6–7.68(m, 3H), 7.78 (s, 1H), 8.19 (s, 1H); Mass Spectrum: M+H⁺ 555.h) The product gave the following data: NMR Spectrum: (CDCl₃) 1.52–1.74(m, 6H), 2.02–2.1 (m, 5H), 2.4 (s, 3H), 2.58–2.6 (m, 2H), 2.76–2.8 (m,2H), 3.18–3.28 (m, 4H), 3.58–3.62 (m, 2H), 3.68–3.72 (m, 2H), 6.68 (d,1H), 6.88 (d, 1H), 7.18 (s, 1H), 7.2–7.32 (m, 2H). 7.44 (s, 1H),7.6–7.68 (m, 3H), 7.78 (s, 1H).S 8.17 (s, 1H), Mass Spectrum: M+H⁺ 569.

EXAMPLE 103–1-Dibenzofuran-4-ylcarbonylamino-2-methylphenyl]-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one

A solution of3-(5-amino-2-methylphenyl)-6-(4-methylpiperazin-1-yl)3,4-dihydroquinazolin-4-one(0.165 g) in DMF (0.5 ml) was added to a stirred mixture ofdibenzofuran-4-carboxylic acid (0.1 g), diisopropyethylamine (0.164 ml),2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate(V) (0.214 g) and DMF (0.5 ml) and the reactionmixture was stirred at ambient temperature for 16 hours. The mixture wasdiluted with water and the resultant solid was isolated, washed in turnwith water and diethyl ether and dried under vacuum at 55° C. There wasthus obtained the title compound (0.228 g); NMR Spectrum: (DMSOd₆) 2.07(s, 3H), 2,25 (s, 3H), 2.5–3.3 (m, 8H), 7.55 (m, 7H), 7.83 (m, 4H), 8.12(s, 1H), 8.21 (d, 1H), 8.34 (d, 1H), 10.59 (s, 1H); Mass Spectrum: M+H⁺544.

EXAMPLE 11

Using an analogous procedure to that described in Example 10,3-(5-amino-2-methylphenyl)-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one,3-(5-amino-2-methylphenyl)-6-(4-methylhomopiperazin-1-yl)-3,4-dihydroquinazolin-4-oneor3-(5-amino-2-methylphenyl)-8-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-onewas reacted with the appropriate carboxylic acid to give the compoundsdescribed in Table V.

TABLE V

No. (R¹)_(m) (R)_(p) Note 1 6-(4-methylpiperazin-1-yl)2-methoxy-3-phenyl a 2 6-(4-methylpiperazin-1-yl) 3-(4-fluorophenyl) b 36-(4-methylpiperazin-1-yl) 3-(2-furyl) c 4 6-(4-methylpiperazin-1-yl)3-cyclopentyloxy d 5 6-(4-methylpiperazin-1-yl) 3-cyclopentyloxy-4- emethoxy 6 6-(4-methylpiperazin-1-yl) 3-acetamido f 76-(4-methylpiperazin-1-yl) 3-(N-methylmethane- g sulphonamido) 86-(4-methylpiperazin-1-yl) 3-(1,1-dioxidoiso- h thiazolidin-2-yl) 96-(4-methylpiperazin-1-yl) 3-morpholino i 10 6-(4-methylpiperazin-1-yl)3-fluoro-4-trifluoro- j methyl 11 6-(4-methylpiperazin-1-yl)3-tetrahydrofuranyloxy k 12 6-(4-methylpiperazin-1-yl) 2-methoxy l 136-(4-methylpiperazin-1-yl) 3-ethoxy m 14 6-(4-methylpiperazin-1-yl)3-(1,1,2,2-tetrafluoro- n ethoxy) 15 6-(4-methylhomopiperazin-1-yl)3-morpholino o 16 6-(4-methylhomopiperazin-1-yl) 3-fluoro-5-morpholino p17 6-(4-methylhomopiperazin-1-yl) 3-morpholino-5-tri- q fluoromethyl 186-(4-methylhomopiperazin-1-yl) 3-(2-furyl) r 198-(4-methylpiperazin-1-yl) 3-morpholino s 20 8-(4-methylpiperazin-1-yl)3-fluoro-5-morpholino t 21 8-(4-methylpiperazin-1-yl)3-morpholino-5-tri- u fluoromethyl 22 8-(4-methylpiperazin-1-yl)3-(2-furyl) v 23 8-(4-methylpiperazin-1-yl) 3-(4-fluorophenyl) wNotesa) The reaction product was purified by column chromatography onreversed-phase silica using initially water and then decreasingly polarmixtures of methanol and water as eluent. There was thus obtained therequired product in 33% yield; NMYR Spectrum: (DMSOd₆) 2.04 (s, 3H)2.27(s, 3H), 2.5–3.3 (m, 8H), 3.42 (s, 3H), 7.54 (mM, 13H), 7.72 (d, 1H),8.09 (s, 1H), 10.52 (s, I N); Mass Spectrum: M+H⁺ 560.

The 2-methoxy-3-phenyl benzoic acid used as a starting material wasprepared as follows:

Methyl iodide (0.409 ml) was added to a stirred mixture of methyl2-hydroxy-3-phenyl benzoate (0.5 g), potassium carbonate (0.606 g) andacetone (5 ml) and the reaction mixture was stirred at 55° C. for 2.5hours. The mixture was evaporated and the residue was partitionedbetween ethyl acetate and water. The organic phase was dried (MgSO₄) andevaporated to give a mixture of the starting material and methyl2-methoxy-3-phenyl benzoate. This mixture was dissolved in DMF (1 ml)and potassium carbonate (0.606 g) and dimethyl sulphate (0.207 ml) wereadded and the resultant reaction mixture was stirred at 80° C. for 16hours. The mixture was partitioned between ethyl acetate and water. Theorganic phase was dried (MgSO₄) and evaporated to give methyl2-methoxy-3-phenyl benzoate (0.458 g) as an oil; NMR Spectrum: (DMSOd₆)3.48 (s, 3H), 3.94 (s, 3H), 7.21 (m, 1H), 7.4 (m, 6H), 7.73 (d, 1H).

A mixture of the material so obtained, 2N aqueous sodium hydroxidesolution (5 ml), methanol (10 ml) and THF (3 ml) was stirred at ambienttemperature for 16 hours. The organic solvents were evaporated and theaqueous reaction mixture was acidified by the addition of 2N aqueoushydrochloric acid solution. The precipitate was isolated, washed withwater and dried under vacuum at 55° C. There was thus obtained2-methoxy-3-phenylbenzoic acid (0.395 g); NMR Spectrum: (DMSOd₆) 3.4 (s,3H), 7.25 (t, 1H), 7.4 (m, 6H), 7.62 (d, 1H), 12.92 (br s, 1H).

b) The starting material 3-(4-fluorophenyl)benzoic acid is described inTetrahedron, 1997, 53, 14437–14450. The product gave the following data:NMR Spectrum: (DMSOd₆) 2.02 (s, 3H), 2.32 (s, 3H), 2.42–2.49 (m, 4H),3.25–3.29 (m, 4H), 7.28–7.38 (m, 2H), 7.41–7.48 (m, 2H), 7.57–7.84 (m,3H), 7.84–7.88 (m, 5H), 7.92 (d, 1H), 8.06 (s, 1H), 8.19 (s, 1H); MassSpectrum: M+H⁺ 548.c) The starting material 3-(2-furyl)benzoic acid is described inTetrahedron Letters, 1998, 39, 4175–4178. The product was purified bycolumn chromatography on an isolute SCX ion exchange column usinginitially methanol and then a 99:1 mixture of methanol and a saturatedaqueous ammonium hydroxide solution as eluent and gave the followingdata: NMR Spectrum: (DMSOd₆) 2.05 (s, 3H), 2.23 (s, 3H), 2.45–2.5 (m,4H), 3.2–3.35 (m, 4H), 6.62 (s, 1H), 7.06 (s, 1H), 7.42 (d, 1H) 7.48 (s,1H), 7.57–7.63 (m, 3H), 7.78–7.84 (m, 4H), 7.9 (d, 1H), 8.08 (s, 1H),8.24 (s, 1H), 10.49 (s, 1H); Mass Spectrum: M+H⁺ 520.d) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.69–1.8(m, 6H), 1.84–1.98 (m, 2H), 2.04 (s, 3H), 2.24 (s, 3H), 2.45–2.5 (m,4H), 3.25–3.29 (m, 4H), 4.86–4.92 (m, 1H), 7.05 (d, 1H), 7.37–7.48 (m,5H), 7.63 (s, 2H), 7.79 (d, 2H), 8.07 (s, 1H), 10.32 (s, 1H); MassSpectrum: M+H⁺ 538.

The 3-cyclopentyloxybenzoic acid used as a starting material wasprepared as follows:

1,1′-Azodicarbonyldipiperidine (6.64 g) was added to a stirred mixtureof cyclopentanol (1.59 ml), ethyl 3-hydroxybenzoate (4.37 g),tributylphosphine (6.48 ml) and THF (100 ml) and the resultant mixturewas stirred at ambient temperature for 16 hours. The mixture wasfiltered and the filtrate was evaporated. The residue was purified bycolumn chromatography on silica using isohexane as eluent. There wasthus obtained ethyl 3-cyclopentyloxybenzoate (4.3 g); Mass Spectrum:M+H⁺ 235.

A mixture of a portion (1 g) of the material so obtained, 2N aqueoussodium hydroxide solution (4.27 ml), methanol (20 ml) and water (5 ml)was stirred at ambient temperature for 4 hours. The mixture wasevaporated and the residue was partitioned between methylene chlorideand water. The aqueous phase was acidified by the addition of 1N aqueoushydrochloric acid solution and extracted with methylene chloride. Theorganic extract was evaporated. There was thus obtained3-cyclopentyloxybenzoic acid (0.864 g); NMR Spectrum: (DMSOd₆) 1.51–1.75(m, 6H), 1.8–2.0 (m, 2H), 4.8–4.86 (m, 1H), 7.12 (d, 1H), 7.34–7.49 (m,2H), 7.46–7.49 (m, 1H), 12.89 (s, 1H).

e) The reaction product was purified by column chromatography onreversed-phase silica using initially water and then decreasingly polarmixtures of methanol and water as eluent. The purified product gave thefollowing data: NMR Spectrum: (DMSOd₆) 1.48–1.62 (m, 2H), 1.64–1.78 (m,4H), 1.8–1.95 (m, 2H), 2.04 (s, 3H), 2.23 (s, 3H), 2.45–2.5 (m, 4H),3.2–3.35 (m, 4H), 3.81 (s, 3H), 7.06 (d, 1H), 7.39 (d, 1H), 7.48 (d, 2H), 7.57–7.63 (m, 3H), 7.77–7.82 (m, 2H), 8.07 (s, 1H), 10.17 (s, 1H);Mass Spectrum: M+H⁺ 568.

The 3-cyclopentyloxy-4-methoxybenzoic acid used as a starting materialis commercially available from Maybridge International, Tintagel,Cornwall, United Kingdom or may be prepared from ethyl3-hydroxy-4-methoxybenzoate using analogous procedures to thosedescribed in Note d) above for the preparation of3-cyclopentyloxybenzoic acid.

t) The reaction product was purified by column chromatography onreversed-phase silica using initially water and then decreasingly polarmixtures of methanol and water as eluent. The purified product gave thefollowing data: NMR Spectrum: (DMSOd₆) 2.04 (s, 3H), 2.05 (s, 3H), 2.22(s, 3H), 2.45–2.5 (m, 4H), 3.2–3.35 (m, 4H), 7.38–7.47 (m, 3H),7.58–7.62 (m, 3H), 7.75–7.81 (m, 3H), 8.05–8.08 (m, 2H), 10.39 (s, 1H);Mass Spectrum: M+H⁺ 511.g) The reaction product was purified by column chromatography onreversed-phase silica using initially water and then decreasingly polarmixtures of methanol and water as eluent. The purified product gave thefollowing data: NMR Spectrum: (DMSOd₆) 2.02 (s, 3H), 2.22 (s, 3H),2.43–2.5 (m, 4H), 2.98 (s, 3H), 3.21–3.3 (m, 4H), 7.4–7.48 (m, 2H),7.52–7.62 (m, 4H), 7.78–7.82 (m, 2H), 7.88 (d, 1H), 7.92 (s, 1H), 8.06(s, 1H), 10.55 (s, 1H); Mass Spectrum: M+H⁺ 561.

The 3-(N-methylmethanesulphonamido)benzoic acid used as a startingmaterial was prepared as follows:

Methanesulphonyl chloride (12.1 ml) was added to a stirred mixture ofethyl 3-aminobenzoate (24.55 g), pyridine (14.42 ml) and methylenechloride (300 ml) and the reaction mixture was stirred at ambienttemperature for 18 hours. The mixture was washed in turn with water, 1Naqueous hydrochloric acid solution and water. The organic phase wasdried (MgSO₄) and evaporated. There was thus obtained ethyl3-methanesulphonamidobenzoate (35.2 g); NMR Spectrum: (DMSOd₆) 1.3 (t,3H), 3.0 (s, 3 H), 4.3 (m, 2H), 7.46 (m, 2H), 7.66 (m, 1H), 7.8 (m, 1H),9.95 (s, 1H), Mass Spectrum: (M−H)⁻ 242.

Methyl iodide (4.23 ml) was added to a stirred mixture of ethyl3-methanesulphonamidobenzoate (15 g), caesium carbonate (22.12 g) andDMF (60 ml) and the reaction mixture was stirred at ambient temperaturefor 1 8 hours. The mixture was partitioned between ethyl acetate andwater. The organic phase was washed with water, dried (MgSO₄) andevaporated. There was thus obtained ethyl3-(N-methylmethanesulphonamido)benzoate (14.87 g); NMR Spectrum:(DMSOd₆) 1.32 (t, 3‘H), 2.95 (s, 3H), 3.26 (s, 3H), 4.32 (m, 2H), 7.55(t, 1H), 7.68 (m, 1H), 7.87 (m, 1H), 7.92 (m, 1H), Mass Spectrum:(M+H)³⁰ 258.

A mixture of the material so obtained, 10N aqueous sodium hydroxidesolution (11.5 ml). ethanol (150 ml) and water (30 ml) was stirred atambient temperature for 4 hours. The mixture was evaporated and 1Naqueous hydrochloric acid solution (125 ml) was added to the residueresulting in the formation of a white precipitate which was isolated,washed in turn with water and diethyl ether and dried under vacuum at60° C. There was thus obtained 3-(N-methylmethanesulphonamido)benzoicacid (9.72 g); NMR Spectrum: (DMSOd₆) 2.94 (s, 3H), 3.26 (s, 3H), 7.52(t, 1H), 7.65 (m, 1H), 7.84 (m, 1H), 7.91 (m, 1H), Mass Spectrum: (M−H)⁻228.

h) The reaction product was purified by column chromatography onreversed-phase silica using initially water and then decreasingly polarmixtures of methanol and water as eluent. The purified product gave thefollowing data: NMR Spectrum: (DMSOd₆) 2.04 (s, 3H), 2.23 (s, 3H),2.4–2.5 (m, 6H), 3.25–3.29 (m, 4H), 3.53 (t, 2H), 3.81 (t, 2H),7.39–7.58 (m, 4H), 7.61 (s, 1H), 7.67–7.68 (m, 2H), 7.78–7.79 (m, 2H),8.07 (s, 1H), 10.43 (s, 1H); Mass Spectrum: M+H⁺ 573.

The 3-(1-dioxidoisothiazolidin-2-yl)benzoic acid used as a startingmaterial was prepared as follows:

3-Chloropropanesulphonyl chloride (5.1) was added dropwise to a stirredmixture of ethyl 3-aminobenzoate (4.5 g), pyridine (2.423 ml),4-dimethylaminopyridine (0.03 g) and methylene chloride (100 ml) and thereaction mixture was stirred at ambient temperature for 48 hours. Themixture was washed with 2N aqueous hydrochloric acid solution and theorganic phase was dried (MgSO₄) and evaporated. There was thus obtainedethyl 3-(3-chloropropanesulphonamido)benzoate (8.19 g); NMR Spectrum:(DMSOd₆) 1.29 (t, 3H), 2.19 (m, 2H), 3.24 (t, 2H), 3.72 (t, 2H), 4.31(m, 2H), 7.47 (m, 2H), 7.68 (m, 1H), 7.83 (m, 1H), 10.12 (s, 1H); MassSpectrum: (M−H )⁻ 303 & 305.

A mixture of the material so obtained, triethylamine (7.3 ml) andethanol (120 ml) was stirred and heated to reflux for 6 hours. Themixture was evaporated. The residue was partitioned between methylenechloride and water. The organic phase was dried (MgSO₄) and evaporated.There was thus obtained ethyl 3-(1,1-dioxidoisothiazolidin-2-yl)benzoate(6.99 g); NMR Spectrum: (DMSOd₆) 1.3 (t, 3H), 2.42 (m, 2H), 3.53 (t,2H), 3.78 (t, 2H), 4.32 (m, 2H), 7.43 (m, 1H), 7.52 (t, 1H), 7.66 (m,1H), 7.78 (m, 1H), Mass Spectrum: (M+H )⁺ 269.

A mixture of a portion (6.87 g) of the material so obtained, 10N aqueoussodium hydroxide solution (5.1 ml). ethanol (80 ml) and water (14 ml)was stirred at ambient temperature for 18 hours. The mixture wasevaporated and 1N aqueous hydrochloric acid solution (160 ml) was addedto the residue resulting in the formation of a white precipitate whichwas isolated, washed in turn with water and diethyl ether and driedunder vacuum at 60° C. There was thus obtained3-(1,1-dioxidoisothiazolidin-2-yl)benzoic acid (5.45 g); NMR Spectrum:(DMSOd₆) 2.43 (m, 2H), 3.5 (t, 2H), 3.78 (t, 2H), 7.39 (m, 1H), 7.48 (t,1H), 7.66 (m, 1H), 7.78 (m, 1H), 13.06 (s, 1H), Mass Spectrum: (M−H)^(')239.

i) The product gave the following data: NMR Spectrum: (DMSOd₆) 2.04 (s,3H), 2.48 (s, 3H), 2.78–2.88 (m, 4H), 3.15–3.19 (m, 4H), 3.28–3.42 (m,4H), 3.73–3.77 (m, 4H) 7.1–7.18 (m, 1H), 7.35–7.42 (m, 4H), 7.51 (s,1H), 7.65 (s, 2H), 7.77–7.8 (m, 2H), 8.1 (s, 1H), 10.29 (s, 1 H); MassSpectrum: M+H⁺ 539.

The 3-morpholinobenzoic acid used as a starting material was prepared asfollows:

A mixture of ethyl 3-bromobenzoate (1.92 ml), morpholine (1.25 ml),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.336 g), sodiumtert-butoxide (1.615 g) and tris(dibenzylideneacetone)dipalladiumn(0)(0.33 g) and toluene (25 ml) was stirred and heated to 90° C. for 18hours under argon. The reaction mixture was allowed to cool to ambienttemperature and extracted with 1N aqueous hydrochloric acid. The aqueousphase was basified with concentrated sodium hydroxide solution andextracted with ethyl acetate. The organic phase was dried (MgSO₄) andevaporated. The residual oil was purified by column chromatography onsilica gel using a 47:3 mixture of methylene chloride and methanol aseluent. There was thus obtained N-(3-morpholinobenzoyl)morpholine (0.45g).

A mixture of the material so obtained, 5M sodium hydroxide solution (2.5ml) and butanol (2 ml) was stirred and heated to 115° C. for 18 hours.The mixture was evaporated and the residue was acidified by the additionof 1N aqueous hydrochloric acid solution (12.5 ml). The resultantprecipitate was isolated, washed with water and dried to give3-morpholinobenzoic acid (0.15 g); NMR Spectrum: (DMSOd₆) 3.1 (t, 4H),3.73 (t, 41H), 7.19 (d, 1H), 7.32 (d, 1H), 7.38 (t, 1H), 7.42 (s, 1H).

j) The product gave the following data: NMR Spectrum: (DMSOd₆) 2.05 (s,3H), 2.26 (s, 3H), 2.47–2.53 (m, 4H), 3.2–3.3 (m, 4H), 7.42–7.48 (m,21H), 7.62 (s, 2H), 7.76–7.8 (m, 2H), 7.93–8.07 (m, 4H), 7.93–8.07 (m,4H), 10.64 (s, 1H); Mass Spectrum: M+H⁺ 540.

k) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.97 (s,3H), 2.18–2.28 (m, 2H), 2.38 (s, 3H), 2.62–2.78 (m, 4H), 3.2–3.41 (m,4H), 3.7–3.92 (m, 4H), 5.04–5.14 (m, 1H), 7.14 (d, 1H), 7.39–7.57 (m,5H), 7.64 (s, 2H), 7.77–7.82 (m, 2H), 8.08 (s, 1H), 10.35 (s, 1H); MassSpectrum: M+H⁺ 540.

The 3-tetrahydrofuranyloxybenzoic acid used as a starting material wasprepared using analogous procedures to those described in Note d) aboveexcept that 3-hydroxytetrahydrofuran was used in place of cyclopentanol.

l) The product gave the following data: NMR Spectrum: (DMSOd₆) 2,05 (s,3H), 2.25 (s, 3H) 2.5 (m, 4H), 3.28 (m, 4H), 3.88 (s, 3H), 7.06 (t, 1H),7.18 (d, 1H), 7.4 (d, 1H), 7.5 (m, 2H), 7.62 (m, 3H), 7.74–7.81 (m, 2H),8.1 (s, 1H), 10.29 (s, 1H); Mass Spectrum: M+H⁺ 484.m) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.34 (t,3H1), 2.05 (s, 3H), 2.25 (s, 3H), 9.5 (m, 4H), 3.25 (m, 4H), 4.08 (q,2H), 7.14 (m, 1H), 7.39–7.55 (m, 5H), 7.64 (m, 2H), 7.8 (m, 2H), 8.1 (s,1H), 10.36 (s, 1H); Mass Spectrum: M+H1 498.n) The product gave the following data: NMR Spectrum: (DMSOd₆) 2.05 (s,3H), 2.25 (s, 3H), 2.5–3.3 (m, 8H), 6.85 (m, 1H), 7.40–7.55 (m, 3H),7.65 (m, 3H), 7.8 (m, 3H),7.98 (m, 1H), 8.1 (s, 1H), 10.55 (s, 1H); MassSpectrum: M+H⁺ 570.o) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.86–1.98(m, 2H), 2.04 (s, 3H), 2.25 (s, 3H), 2.42–2.5 (m, 2H), 2.62–2.66 (m,2H), 3.15–3.19 (m, 4H), 3.53 (t, 2H), 3.58–3.64 (m, 2H), 3.72–3.76 (m,4H), 7.1–7.18 (m, 1H), 7.24 (s, 1H), 7.34–7.44 (m, 5H), 7.58 (d, 1H),7.76–7.82 (m, 2H), 7.96 (s, 1H), 10.29 (s, 1H); Mass Spectrum: M+H⁺ 553.p) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.86–1.98(m, 2H), .2.04 (s, 3H), 2.25 (s, 3H), 2.42–2.5 (m, 2H), 2.62–2.66 (m,2H), 3.19–3.23 (m, 4H), 3.53 (t, 2H), 3.58–3.64 (m, 2H), 3.71–3.75 (m,4H), 6.98 (d, 1H), 7.12 (d, 1H), 7.24 (s, 1H), 7.28 (s, 1H), 7.32–7.44(m, 2H), 7.58 (d, 1H), 7.74–7.82 (m, 2H), 7.96 (s, 1H), 10.32 (s, 1H);Mass Spectrum: M+H⁺ 571.

The 3-fluoro-5-morpholinobenzoic acid used as a starting material wasprepared as follows:

A mixture of ethyl 3-fluoro-5-morpholinobenzoate (Tetrahedron, 1999, 55,13285–13300; 6.7 g), 10M sodium hydroxide solution (13.6 ml), water(13.6 ml) and ethanol (67 ml) was stirred at ambient temperature for 20hours. The mixture was concentrated by evaporation and the residue wasacidified by the addition of concentrated hydrochloric acid. Theresultant precipitate was isolated, washed with water and dried to give3-fluoro-5-morpholinobenzoic acid (5.7 g); NMR Spectrum: (DMSOd₆) 3.16(t, 4H), 3.71 (t, 4H), 7.01 (m, 2H), 7.27 (s, 1H).

q) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.86–1.98(m, 2H), 2.05 (s, 3H), 2.25 (s, 3H), 2.42–2.5 (m, 2H), 2.62–2.66 (m,2H), 3.24–3.34 (m, 4H), 3–53 (t, 2H1), 3.58–3.64 (m, 2H),3.73–3.77 (m,4H), 7.24 (s, 1H), 7.32–7.43 (m, 3H), 7.58 (d, 1H), 7.63 (s, 1H), 7.7(s, 1H), 7.74 (s, 1H),. 7.8 (d, 1H), 7.97 (s, 1H), 10.45 (s, 1H); MassSpectrum: M+H⁺ 621.r) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.86–1.98(m, 2H), 2.05 (s, 3H), 2.25 (s, 3H), 2.42–2.5 (m, 2H), 2.62–2.66 (m,2H), 3.53 (t, 2H), 3.58–3.64 (m, 2H), 6.61 (s, 1H), 7.04 (s, 1H), 7.24(s, 1H), 7.38 (d, 1H), 7.42 (d, 1H), 7.52–7.6 (m, 2H), 7.78–7.92 (m,5H), 7.98 (s, 1H), 8.24 (s, 1H), 10.49 (s, 1H); Mass Spectrum: M+H³⁰534.s) The reaction residue was purified by column chromatography on an SCXisolute ion exchange column using initially methanol and then a 99:1mixture of methanol and a saturated aqueous ammonium hydroxide solutionas eluent. The material so obtained was dissolved in acetone andprecipitated by the addition of isohexane. The product so obtained gavethe following data: NMR Spectrum: (DMSOd₆) 2.05 (s, 3H), 2.25 (s, 3H),3.3–3.4 (m, 4H), 3.7–3.8 (m, 4H), 7.1–7.2 (m, 1H), 7.3–7.5 (m, 7H),7.75–7.85 (m, 3H), 8.25 (s, 1H), 10.3 (s, 1H); Mass Spectrum: M+H⁺ 539.

The3-(5-amino-2-methylphenyl)-8-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-oneused as a starting material was prepared as follows:

Oxalyl chloride (8.5 ml) was added dropwise to a stirred solution of3-chloro-2-nitrobenzoic acid (15.1 g) in a mixture of methylene chloride(200 ml) and DMF (a few drops) which had been cooled to 0° C. Themixture was allowed to warm to ambient temperature and was stirred for afurther 16 hours. The solvent was evaporated. The residue was dissolvedin methylene chloride (300 ml) and added dropwise to a stirred mixtureof 2-methyl-5-nitroaniline (10.6 g), triethylamine (27.2 ml) andmethylene chloride (300 ml). The resultant mixture was stirred atambient temperature for 16 hours. The precipitate was isolated, washedin turn with a saturated aqueous sodium bicarbonate solution and diethylether and dried under vacuum at 40° C. There was thus obtainedN-(2-methyl-5-nitrophenyl)-3-chloro-2-nitrobenzamide (14.2 g); NMRSpectrum: (DMSOd₆) 2.37 (s, 3H), 7.57 (d, 1H), 7.8–7.85 (m, 1H)7.95–8.05 (m, 3H), 8.35 (m, 1H)); Mass Spectrum: M+H⁺ 335.

A mixture of the material so obtained and N-methylpiperazine (24.5 ml)was stirred and heated to 100° C. for 16 hours. The reaction mixture wascooled to ambient temperature and poured into water. The resultantprecipitate was isolated, washed with water and dried under vacuum at40° C. There was thus obtainedN-(2-methyl-5-nitrophenyl),-(4-methylpiperazin-1-yl)-2-nitrobenzamide(11.8 g); NMR Spectrum: (DMSOd₆) 2.2 (s, 3H) 2.35–2.45 (m, 7H), 2.9–3.0(m, 4H), 7.5–7.7 (m, 4H), 8.0–8.05 (m, 1H), 8.3 (s, 1H); Mass Spectrum:M+H⁺ 400.

A mixture of the material so obtained, 10% palladium-on-carbon catalyst(1.2 g) and methanol (600 ml) was stirred under an atmosphere ofhydrogen gas until hydrogen uptake ceased. The catalyst was filtered offand the filtrate was evaporated. The material so obtained was purifiedby column chromatography on silica using a 4:1 mixture of methylenechloride and methanol as eluent. There was thus obtainedN-(5-amino-2-methylphenyl)-2-amino-3-(4-methylpiperazin-1-yl)benzamide(7.36 g); NMR Spectrum: (DMSOd₆) 2.0 (s, 3H), 2.2 (s, 3H), 2.75–2.85 (m,4H), 4.85 (s, 2H), 6.0 (s, 2H), 6.35–6.4 (m, 1H), 6.57 (m, 2H), 6.85 (d,1H), 7.07 (d, 1H), 7.45 (d, 1H), 9.35 (s, 1H); Mass Spectrum: M+H⁺ 340.

A mixture of a portion (4 g) of the material so obtained, triethylorthoformate (3.92 ml), glacial acetic acid (0.34 ml) and ethanol (72ml) was stirred and heated to 80° C. for 2 days. The reaction mixturewas cooled and evaporated. The residue was dissolved in water, basifiedby the addition of sodium bicarbonate and extracted with methylenechloride. The organic extract was evaporated and the residue waspurified by column chromatography on silica using a 20:1 mixture ofmethylene chloride and methanol as eluent. There was thus obtained3-(5-amino-2-methylphenyl)-8-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one(4.1 g); NMR Spectrum: (DMSOd₆) 1.85 (s, 3H), 2.2 (s, 3H), 2.5–2.6 (m,4H), 5.15 (s, 2H), 6.5 (d, 1H), 6.6–6.65 (m, 1H), 7.0 (d, 1H), 7.3 (d,1H), 7.42 (t, 1H), 7.75 (d, 1H), 8.15 (s, 1H); Mass Spectrum: M+H⁺ 350.

t) The product gave the following data: NMR Spectrum: (DMSOd₆) 2.05 (s,3H), 2.25 (s, 3H), 3.2–3.25 (m, 4H), 3.7–3.8 (m, 4H), 6.95–7.0 (m, 1H),7.1–7.15 (m, 1H), 7.3–7.4 (m, 2H), 7.4–7.5 (m, 2H), 7.75–7.8 (m, 3H),8.25 (s, 1H), 10.33 (s, 1H); Mass Spectrum: M+H⁺ 557.u) The product gave the following data NMR Spectrum: (DMSOd₆) 2.05 (s,3H1), 2.25 (s, 3H), 3.7–3.8 (m, 4H), 7.3–7.5 (m, 4H), 7.6–7.85 (m, 5H),8.25 (s, 1H), 10.48 (s, 1H); Mass Spectrum: M+H⁺ 607.v) The product gave the following data: NMR Spectrum: (DMSOd₆) 2.05 (s,3H), 2.25 (s, 3H), 6.6–6.65 (m, 1H), 7.05 (m, 1H), 7.3–7.35 (m, 1H),7.4–7.5 (m, 2H), 7.5–7.6 (m, 1H), 7.75–7.95 (m, 6H), 8.25–8.3 (m, 2H),10.5 (s, 1H); Mass Spectrum: M+H⁺ 520.w) The product Pave the following data: NMR Spectrum: (DMSOd₆) 2.05 (s,3H), 2.25 (s, 3H), 7.3–7.4 (m, 3H), 7.4–7.5 (m, 2H), 7.55–7.65 (m, 1H),7.75–7.95 (m, 7H), 8.18 (s, 1H), 8.3 (s, 1H), 10.48 (s, 1H); MassSpectrum: M+H⁺ 548.

EXAMPLE 12

Using an analogous procedure to that described in Example 1 or Example 2as appropriate, the appropriate 2-aminobenzamide was reacted withtriethyl orthoformate or triethyl orthoacetate to give the compoundsdescribed in Table VI.

TABLE VI

No. (R¹)_(m) (R²)_(n) R³ (R)_(p) Note 1 8-morpholino 4-methyl H3-(4-methylpiper- a azin-1-yl)methyl 2 8-morpholino 4-methyl methyl3-(4-methylpiper- b azin-1-yl)methylNotesa) The reaction mixture was heated to 70° C. for 48 hours. The productgave the following data: NMR Spectrum: (DMSOd₆) 2.1 (s, 3H), 2.2–2.45(m, 1H), 3.5 (s, 2H), 3.7–3.8 (m, 4H), 7.3–7.35 (m, 2H), 7.4–7.55 (m,4H), 7.55–7.6 (m, 1H), 7.8 (d, 1H), 7.8–7.9 (m, 2H), 8.3 (s, 1H), 10.0(s, 1H); Mass Spectrum: M+H⁺ 553.

TheN-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-methylphlenyl}-2-amino-3-morpholinobenzamideused as a starting material was prepared as follows:

3-Chloromethylbenzoyl chloride (24.8 ml) was added to a stirred mixtureof 2-methyl5-nitroaniline (26.6 g), triethylamine (49 ml) and methylenechloride (800 ml) and the mixture was stirred at ambient temperature for16 hours. The precipitate was isolated, washed with 1N aqueoushydrochloric acid solution and with diethyl ether and dried under vacuumat 40° C. There was thus obtained3-chloromethyl-N-(2-methyl-5-nitrophenyl)benzamide (43.5 g); NMRSpectrum: (DMSOd₆) 2.38 (s, 3H), 2.85 (s, 2H), 7.53–7.58 (m, 2H), 7.67(d, 1H) 7.95(d, 1H), 8.01–8.04 (m, 2H), 8.32 (s, 1H), 10.19 (s, 1H);Mass Spectrum: M+H⁺ 305.

1-Methylpiperazine (8.03 ml) was added to a stirred mixture of a portion(20 g) of the material so obtained, potassium carbonate (18.2 g) andacetone (750 ml) and the mixture was heated to 54° C. and stirred for 16hours. The resultant solution was evaporated and the residue wasdissolved in methylene chloride. The organic solution was washed withwater and evaporated. There was thus obtainedN-(2-methyl-5-nitrophenyl)-3-(4-methylpiperazin-1-ylmethyl)benzamide(26.4 g); NMR Spectrum: (DMSOd₆) 2.06 (s, 3H), 2.12 (s, 3H), 2.31–2.37(m, 8H), 3.52 (s, 2H), 7.48–7.57 (m, 3H), 7.87 (d, 2H), 8.01 (m, 1H),8.33 (s, 1H); Mass Spectrum: M+H⁺ 369.

Iron powder was added to a stirred mixture of a portion (18.0 g) of thematerial so obtained, ethanol (500 ml), water (50 ml) and acetic acid(10 ml). The resultant mixture was stirred and heated to reflux for 5hours. Water (50 ml) was added and the mixture was basified by theaddition of sodium carbonate. The mixture was filtered and the filtratewas evaporated to dryness. The residue was triturated under water andthe resultant solid was isolated and dried under vacuum at 40° C. Therewas thus obtainedN-(5-amino-2-methylphenyl)-3-(4-methylpiperazin-1-ylmethyl)benzamide(11.1 g); NMR Spectrum: (DMSOd₆) 2.03 (s, 3H), 2.13 (s, 3H), 2.24–2.4(m, 8H), 3.5 (s, 2H), 4.86 (s, 2H) 6.35 (d, 1H), 6.57 (s, 1H), 6.86 (d,1H), 7.40–7.48 (m, 2H), 7.78–7.83 (m, 2H), 9.57 (s, 1H); Mass Spectrum:M+H⁺ 339.

Oxalyl chloride (0.83 ml) was added to a mixture of3-chloro-2-nitrobenzoic acid (1.45 g), methylene chloride (30 ml) and afew drops of DMF which had been cooled to 0° C. The reaction mixture wasstirred at ambient temperature for 4 hours. The mixture was evaporated.The residue was dissolved in methylene chloride (10 ml) and a portion (5ml) of the solution was added to a mixture ofN-(5-amino-2-methylphenyl)-3-(4-methylpiperazinyl-ylmethyl)benzamide(1.01 g), triethylamine (1 ml) and methylene chloride (20 ml). Theresultant mixture was stirred at ambient temperature for 16 hours. Themixture was evaporated and the residue was partitioned between methylenechloride and a saturated aqueous sodium bicarbonate solution. Theorganic phase was dried (MgSO₄) and evaporated. There was thus obtainedN-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-methylphenyl}-3-chloro-2-nitrobenzamide(1.69 g); NMR Spectrum: (DMSOd₆) 2.15 (s, 3H), 2.2 (s, 3H), 2.2–2.4 (m,8H), 3.5 (s, 2H), 7.2–7.3 (m, 1H), 7.4–7.5 (m, 3H), 7.7–7.95 (m, 6H),9.9 (s, 1H), 10.78 (s, 1H); Mass Spectrum: M+H⁺ 522.

A mixture of the material so obtained and morpholine (2.71 ml) wasstirred and heated to 105° C. for 16 hours. The mixture was cooled toambient temperature and poured into water. The precipitate was isolated,washed with water and partitioned between a saturated aqueous sodiumbicarbonate solution and methylene chloride. The organic phase was dried(MgSO₄) and evaporated. There was thus obtainedN-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-methylphenyl}-2-nitro-3-morpholinobenzamide(1.47 g); NMR Spectrum: (DMSOd₆) 2.15 (s, 3H), 2.2 (s, 3H), 2.2–2.45 (m,8H), 2.85–2:95 (m, 4H), 3.5 (s, 2H), 3.6–3.7 (m, 4H), 7.2 (d, 1H),7.4–7.5 (m, 3H), 7.5–7.6 (m, 1H), 7.6–7.7 (m, 2H), 7.75 (s, 1H), 7.8–7.9(m, 2H), 9.9 (s, 1H), 10.62 (s, 1H); Mass Spectrum: M+H⁺ 573.

A mixture of the material so obtained, iron powder (1.435 g), ethanol(25.7 ml), water (2.57 ml) and glacial acetic acid (0.52 ml) was stirredand heated to 95° C. for 8 hours. The resultant mixture was cooled toambient temperature and basified to pH9 by the addition of sodiumbicarbonate. The mixture was filtered and the filtrate was evaporated.The residue was partitioned between ethyl acetate and a saturatedaqueous sodium bicarbonate solution. The organic phase was dried (MgSO₄)and evaporated. The material so obtained was dissolved in ethyl acetateand precipitated by the addition of isohexane. The solid was isolated.There was thus obtainedN-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-methylphenyl}-2-amino-3-morpholinobenzamide(0.95 g); NMR Spectrum: (DMSOd₆) 2.1 (s, 3H), 2.2 (s, 3H), 2.2–2.4 (m,8H), 2.75–2.8 (m, 4H), 3.5 (s, 2H), 3.7–3.8 (m, 4H), 6.05 (s, 2H), 6.6(t, 1H), 7.1 (d, 1H), 7.2 (d, 1H), 7.4–7.5 (m, 4H), 7.8 (d, 1H), 7.8–7.9(m, 2H), 9.85 (s, 1H), 9.95 (s, 1H); Mass Spectrum: M+H⁺ 543.

b) The reaction mixture was heated to 70° C. for 48 hours. The productgave the following data: NMR Spectrum: (DMSOd₆) 2.1 (s, 3H), 2.2 (s,3‘H), 2.2–2.4 (m, 1H), 3.5 (s, 2H), 3.7–3.85 (m, 4H), 7.2–7.3 (m, 2H),7.3–7.5 (m, 5H), 7.65 (d, 1H), 7.8–7.9 (m, 2H), 10.0 (s, 1H); MassSpectrum: M+H⁺ 567.

EXAMPLE 13

Using an analogous procedure to that described in Example 1 or Example 2as appropriate, the appropriate 2-aminobenzamide was reacted withtriethyl orthoformate or triethyl orthoacetate to give the compoundsdescribed in Table VII. In each case the reaction product was purifiedby column chromatography on an isolute SCX ion exchange column usinginitially methanol and then a 99:1 mixture of methanol and a saturatedaqueous ammonium hydroxide solution as eluent.

TABLE VII

No. (R¹)_(m) R³ (R)_(p) Note 1 6-(4-methylpiperazin-1-yl) methyl3-fluoro-5- a morpholino 2 6-(4-methylpiperazin-1-yl) H 3-fluoro-5- bmorpholino 3 6-[N-(3-dimethylaminopropyl)- methyl 3-fluoro-5- cN-methylamino] morpholino 4 6-[N-(3-dimethylaminopropyl)- H 3-fluoro-5-d N-methylamino] morpholino 5 6-(3-dimethylaminopropylamino) methyl3-fluoro-5- e morpholino 6 6-(3-dimethylaminopropylamino) H 3-fluoro-5-f morpholino 7 6-[N-(3-methylaminopropyl)- methyl 3-fluoro-5- gN-methylamino] morpholino 8 6-[N-(3-methylaminopropyl)- H 3-fluoro-5- hN-methylamino] morpholinoNotesa) The product gave the following data: Mass Spectrum: M+H⁺ 591.

The3-[2-amino-5-(4-methylpiperazin-1-yl)benzamido]-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamideused as a starting material was prepared as follows:

A mixture of 3,5-difluoronitrobenzene (31.1 g) and morpholine (85.2 g)was stirred and heated at 100° C. for 66 hours. The mixture wasevaporated and the residue was purified by column chromatography onsilica gel using a 4:1 mixture of isohexane and ethyl acetate as eluent.There was thus obtained 3-fluoro-5-morpholinonitrobenzene (33.3 g); NMRSpectrum: (DMSOd₆) 3.2–3.3 (m, 4H), 3.6–3.8 (m, 4H), 7.25 (m, 1H), 7.37(m, 1H), 7.5 (m, 1H).

A mixture of the material so obtained, 10% palladium-on-carbon (3.3 g)and ethanol (1400 ml) was stirred under an atmosphere pressure ofhydrogen gas for 16 hours. The mixture was filtered and the filtrate wasevaporated to give 3-fluoro-5-morpholinoaniline (27.5 g); NMR Spectrum:(DMSOd₆) 2.9–3.05 (m, 4H), 3.6–3.7 (m, 4H), 5.15 (s, 2H), 5.75–5.9 (m,3H).

A solution of 4-chloro-3-nitrobenzoyl chloride (41.2 g) in methylenechloride (120 ml) was added to a mixture of 3-fluoro-5-morpholinoaniline(27 g), triethylamine (52.6 ml) and methylene chloride (600 ml) whichhad been cooled in an ice-bath. The resultant mixture was stirred atambient temperature for 16 hours. The mixture was evaporated. Methylenechloride and a saturated aqueous sodium bicarbonate solution were addedand the resultant precipitate was isolated, washed with diethyl etherand dried under vacuum. There was thus obtained4-chloro-3-nitro-N-(3-fluoro-5-morpholinophenyl)benzamide (36.1 g); NMRSpectrum: (DMSOd₆) 3.05–3.15 (m, 4H), 3.7–3.75 (m, 4H), 6.5–6.6 (m, 1H),7.1–7.2 (m, 2H), 7.95 (d, 1 H), 8.2–8.3 (m, 1H), 8.6 (s, 1 H).

A mixture of the material so obtained, iron powder (50.6 g), glacialacetic acid (19 ml), water(95 ml) and ethanol (600 ml) was stirred andheated to reflux for 6 hours. The mixture was cooled to ambienttemperature and water was added. The mixture was carefully basified topH9 by the addition of a saturated aqueous sodium bicarbonate solutionand extracted with ethyl acetate. The organic phase was dried overmagnesium sulphate and evaporated to give3-amino-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide (24.3 g); NMRSpectrum: (DMSOd₆) 3.0–3.1 (m, 4H), 3.7–3.75 (m, 4H), 5.6 (s, 1H),6.45–6.55 (m, 1H), 5 7.0–7.2 (m, 3H), 7.3–7.35 (m, 2H), 10.09 (br s,1H)-Mass Spectrum: M+H⁺ 350.

Oxalyl chloride (1.05 ml) was added dropwise to a stirred mixture of5-chloro-2-nitrobenzoic acid (2.08 g), methylene chloride (100 ml) andDMF (a few drops) which had been cooled to 0° C. The mixture was allowedto warm to ambient temperature and was stirred for 4 hours. The mixturewas evaporated and the residue was dissolved in methylene chloride (10ml) and added dropwise to a stirred mixture of3-amino-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide (3.0 g) andpyridine (40 ml). The resultant mixture was heated at 80° C. for 16hours. The solvent was evaporated and the residue was dissolved inmethylene chloride (50 ml) and water (50 ml) and stirred for one hour.The resultant solid was filtered, washed with water and diethyl etherand dried under vacuum at 40° C. There was thus obtained4-chloro-3-(5-chloro-2-nitrobenzamido)-N-(3-fluoro-5-morpholinophenyl)benzamide(1.07 g); NMR Spectrum: (DMSOd₆) 3.09–3.14 (m, 4H), 3.69–3.74 (m, 4H),6.58 (d, 1H), 7.15–7.2 (m, 2H), 7.71 (d, 1H), 7.82–7.92 (m, 3H), 8.2 (d,1H), 8.29 (s, 1H), 10.37 (s, 1H), 10.61 (s, 1H); Mass Spectrum: M+H⁺533and 535.

A portion (0.8 g) of the material so obtained was dissolved in1-methylpiperazine (3 ml) and the mixture was stirred and heated to 100°C. for 16 hours. The mixture was cooled and poured into water. Theresultant solid was isolated, washed in turn with water and diethylether and dried under vacuum at 40° C. There was thus obtained4-chloro-N-(3-fluoro-5-morpholinophenyl)-3-[5-(4-methylpiperazin-1-yl)-2-nitrobenzamido]benzamide(0.803 g); NMR Spectrum: (DMSOd₆) 2.21 (s, 3H), 2.4–2.45 (m, 4H),3.08–3.13 (m, 4H), 3.46–3.5 (m, 4H), 3.69–3.74 (m, 4H), 6.58 (d, 1H),6.84 (s, 1H), 7.0–7.2 (m, 4H), 7.68 (d, 1H), 7.80 (d, 1H), 8.04 (d, 1H),8.36 (s, 1H); Mass Spectrum: M+H⁺ 597.

Iron powder (0.726 g) was added to a stirred suspension of4-chloro-N-(3-fluoro-5-morpholinophenyl)-3-[5-(4-methylpiperazin-1-yl)-2-nitrobenzamido]benzamide(0.76 g), water (2 ml), acetic acid (0.5 ml) and ethanol (15 ml) and theresultant mixture was stirred and heated to reflux for 1 hour. Themixture was cooled to ambient temperature. Water (80 ml) was added andthe mixture was basified by the addition of sodium carbonate. Theresultant mixture was filtered through diatomaceous earth and theseparated solids were washed in turn with methylene chloride andmethanol. The combined filtrates were evaporated and the residue wastriturated under ethyl acetate. The mixture was filtered and thefiltrate was evaporated to give3-[2-amino-5-(4-methylpiperazin-1-yl)benzamido]-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide(0.385 g); Mass Spectrum: M+H⁺ 567.

b) The product gave the following data: Mass Spectrum: M+H⁺ 577.

c) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.6–1.7(m, 2H), 2.09 (s, 3H), 2.11 (s, 6H), 2.21 (t, 2H), 2.96 (s, 3H),3.06–3.14 (m, 4H), 3.37–3.43 (m, 2H), 3.69–3.8 (m, 4H), 6.56 (d, 1H),7.09 (s, 1H), 7.15–7.19 (m, 2H) 7.32–7.38 (m, 1H), 7.53 (d, 1H), 7.9 (d,1H), 8.09 (d, 1H), 8.16 (s, 1H), 10.31 (s, 1H); Mass Spectrum: M+H⁺ 607.

The3-{-amino-5-[N-(3-dimethylaminopropyl)-N-methylamino]benzanido]-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamideused as a starting material was prepared as follows:

A mixture of4-chloro-3-(5-chloro-2-nitrobenzamido)-N-(3-fluoro-5-morpholinophenyl)benzamide(0.8 g) and N-(3-dimethylaminopropyl)-N-methylamine (3 ml) was stirredand heated to 100° C. for 16 hours. The mixture was cooled and pouredinto water. The resultant solid was isolated, washed in turn with waterand-diethyl ether and dried under vacuum at 40° C. There was thusobtained4-chloro-3-{5-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamidol}-N-(3-fluoro-5-morpholinophenyl)benzamide;NMR Spectrum: (DMSOd₆) 1.62–1.74 (m, 2H), 2.12 (s, 6H), 2.21 (t, 2H),3.08 (s, 3H), 3.1–3.13 (m, 4H), 3.52 (t, 2H), 3.71–3.74 (m, 4H), 6.68(d, 1H), 6.78 (s, 1H), 6.84 (d, 1H), 7.16–7.20 (m, 2H), 7.68 (d, 1H),7.82 (d, 1H), 8.04 (d, 1H), 8.31 (s, 1H); Mass Spectrum: M+H⁺613 and615.

Using an analogous procedure to that described in the last paragraph ofthe portion of Note a) immediately above which is concerned with thepreparation of starting materials,4-chloro-3-{5-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamido}-N-(3-fluoro-5-morpholinophenyl)-benzamidewas reduced to give3-{2-amino-5-N-(3-dimethylaminopropyl)-N-methylamino]benzamido]-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide;NMR Spectrum: (DMSOd₆) 1.54–1.62 (m, 2H), 2.1 (s, 6H), 2.18–2.22 (m,2H), 2.77 (s, 3H), 3.09–3.16 (m, 4H), 3.18–3.22 (m, 2H), 3.7–3.74 (m,4H), 6.57 (d, 1H), 6.7 (d, 1H), 6.84 (d, ]H), 7.08–7.24 (m, 3H), 7.7 (d,1H), 7.8 (d, 1H), 8.27 (s, 1H); Mass Spectrum: M+H⁺ 583.

d) The product gave the following data: Mass Spectrum: M+H⁺ 593.

c) The product gave the following data: Mass Spectrum: M+H⁺ 593.

The3-[2-amino-5-(3-dimethylaminopropylamino)benzamido]-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamideused as a starting material was prepared as follows:

Using an analogous procedure to that described in the sixth paragraph ofthe portion of Note a) immediately above which is concerned with thepreparation of starting materials.4-chloro-3-(5-chloro-2-nitrobenzamido)-N-(3-fluoro-5-morpholinophenyl)benzamidewas reacted with 3-dimethylaminopropylamine to give4-chloro-3-[5-(3-dimethylaminopropylamino)-2-nitrobenzamido]-N-(3-fluoro-5-morpholinophenyl)benzamidein 76% yield; NMR Spectrum: (DMSOd₆) 1.62–1.74 (m, 2H), 2.12 (s, 6H),2.27 (t, 2H), 3.08–3.13 (m, 4H), 3.18–3.22 (m, 2H), 3.69–3.74 (m, 4H),6.58 (d, 1H) 6.67 (m, 2H), 7.15–7.2 (m, 2H), 7.42 (t, 1H), 7.69 (d, 1H),7.68 (d, 1H), 7.82 (d, 1H), 8.04 (d, 1H), 8.26 (s, 1H), 10.32 (s, 1H);Mass Spectrum: M+H⁺ 599.

Using an analogous procedure to that described in the last paragraph ofthe portion of Note a) immediately above which is concerned with thepreparation of starting materials,4-chloro-3-[5-(3-dimethylaminopropylamino)-2-nitrobenzamido]-N-(3-fluoro-5-morpholinophenyl)benzamidewas reduced to give the required starting material; NMR Spectrum:(DMSOd₆) 1.62–1.78 (m, 2H), 2.15 (s, 6H), 2.33 (t, 2H), 2.99 (t, 2H),3.09–3.13(m, 4H), 3.69–3.74 (m, 4H), 6.56 (d, 1H), 6.66 (s, 2H), 6.94(s, 1H), 7.15–7.22 (m, 3H), 7.68 (d, 1H), 7.78 (d, 1H), 8.32 (s, 1 H),10.29 (s, 1 H); Mass Spectrum: M+H⁺ 569.

i) The product gave the following data: Mass Spectrum: M+H⁺ 579.

g) The product gave the following data: Mass Spectrum: M+H⁺ 593.

The3-{2-amino-5-[N-(3-methylaminopropyl)-N-methylamino]benzamido]-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamideused as a starting material was prepared as follows:

Using an analogous procedure to that described in the sixth paragraph ofthe portion of Note a) immediately above which is concerned with thepreparation of starting materials,4-chloro-3-(5-chloro-2-nitrobenzamido)-N-(3-fluoro-5-morpholinophenyl)benzamidewas reacted with N-(3-methylaminopropyl)-N-methylamine to give4-chloro-3-(5-chloro-2-nitrobenzamido)-N-(3-fluoro-5-morpholinophenyl)benzamide;NMR Spectrum: (DMSOd₆) 1.62–1.74 (m, 2H), 2.25 (s, 3H), 2.46–2.49 (m,2H), 3.07 (s, 3H) 3.12 (t, 2H), 3.55 (t, 2H), 3.69–3.74 (m, 4H), 6.58(d, 1H) 6.79 (s, 1H), 6.86 (d, 1H), 7.16–7.2 (m, 2H), 7.69 (d, 1H), 7.82(d, 1H), 8.12 (s, 1H); Mass Spectrum: M+H⁺ 599.

Using an analogous procedure to that described in the last paragraph ofthe portion of Note a) immediately above which is concerned with thepreparation of starting materials,4-chloro-N-(3-fluoro-5-morpholinophenyl)-3-{5-[N-(3-methylaminopropyl)-N-metlhlylamino]-2-nitrobenzamido}benzamidewas reduced to give3-{2-amino-5-[N-(3-methylaminopropyl)-N-methylamino]benzamido]-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide;Mass Spectrum: M+H⁺ 569 and 571.

h) The product gave the following data: Mass Spectrum: M+H⁺ 579.

EXAMPLE 143-{3-[N-(3-fluoro-5-morpholinophenyl)carbamoyl]phenyl}-8-[N-(3-dimethylaminopropyl)-N-methylamino]-3,4-dihydroquinazolin-4-one

Using an analogous procedure to that described in Example 1,3-{2-amino[-3-(3dimethylaminopropyl)-N-methylamino]benzamido]-N-(3-fluoro-5-morpholinophenyl)benzamidewas reacted with triethyl orthoformate. The reaction product waspurified by column chromatography on an isolute SCX ion exchange columnusing initially methanol and then a 99:1 mixture of methanol and asaturated aqueous ammonium, hydroxide solution as eluent. There was thusobtained the title compound Mass Spectrum: M+H⁺ 559.

The3-{2-amino-3-[N-(3-dimethylaminopropyl)-N-methylamino]benzamido]-N-(3-fluoro-5-morpholinophenyl)benzamideused as a starting material was prepared as follows:

Oxalyl chloride (0.51 g) was added dropwise to a stirred mixture of3-chloro-2-nitrobenzoic acid (0.694 g), methylene chloride (50 ml) andDMF (a few drops) which had been cooled to 0° C. The mixture was allowedto warm to ambient temperature and was stirred for 4 hours. The mixturewas evaporated and the residue was dissolved in methylene chloride (10ml) and added dropwise to a stirred mixture of3-amino-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide (1.0 g) andpyridine (20 ml). The resultant mixture was heated at 80° C. for 16hours. The solvent was evaporated and the residue was dissolved inmethylene chloride (50 ml) and water (50 ml) and stirred for one hour.The resultant solid was filtered, washed with water and diethyl etherand dried under vacuum at 40° C. There was thus obtained4-chloro-3-(3-chloro-2-nitrobenzamido)-N-(3-fluoro-5-morpholinophenyl)benzamide(1.07 g); NMR Spectrum: (DMSOd₆) 3.09–3.13 (m, 4H), 3.5–3.74 (m, 4H),6.48 (d, 1H), 7.14–7.21 (m, 2H), 7.63 (d, 1H), 7.7–7.77 (m, 2H), 7.89(d, 1H), 8.04 (d 1H), 8.14 (s, 1H), 10.27 (s, 1H), 10.8 (s, 1H); MassSpectrum: M+H⁺ 533 and 535.

A mixture of4-chloro-3-(3-chloro-2-nitrobenzamido)-N-(3-fluoro-5-morpholinophenyl)benzamide(0.51 g) and N-(3-dimethylaminopropyl)-N-methylamine (2 ml) was stirredand heated to 100° C. for 16 hours. The mixture was cooled and pouredinto water. The resultant solid was isolated, washed in turn with waterand diethyl ether and dried under vacuum at 40° C. There was thusobtained4-chloro-3-{3-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamido}-N-(3-fluoro-5-morpholinophenyl)benzamide(0.45 g); NMR Spectrum: (DMSOd₆) 1.48–1.58 (m, 2H), 2.07 (s, 6H), 2.15(t, 2H), 2.69 (s, 3H), 3.03 (t, 2H), 3.08–3.15 (m, 4H), 3.7–3.75 (m,4H), 6.74 (d, 1H), 7.15–7.2 (m, 2H), 7.44 (d, 1H), 7.52–7.64 (d, 2H),7.7 (d, 1H), 7.82 (d, 1H), 8.08 (s, 1H), 10.32 (s, 1H); Mass Spectrum:M+H⁺ 613 and 615.

A mixture of a portion (0.25 g) of the material so obtained, 10%palladium-on-carbon (0.025 g) and methanol (25 ml) was stirred under anatmosphere of hydrogen gas. After cessation of hydrogen uptake, thecatalyst was removed by filtration through diatomaceous earth and thefiltrate was evaporated. The reaction product was purified by columnchromatography on an isolute SCX ion exchange column using initiallymethanol and then a 99:1 mixture of methanol and a saturated aqueousammonium hydroxide solution as eluent. There was thus obtained3-{2-amino-3-[-(3-dimethylaminopropyl)-N-methylamino]benzamido]-N-(3-fluoro-5-morpholinophenyl)benzamide(0. 102 g); NMR Spectrum: (DMSOd₆) 1.58–1.62 (m, 2H), 2.09 (s, 6H), 2.25(t, 21) 2.56 (s, 3H), 2.77 (t, 2H), 3.09–3.13 (m, 6H), 3.7–3.73 (m, 4H),6.39 (s, 1H), 6.48–6.64 (m, 3H), 7.08–7.24 (m, 4H), 7.4–7.5 (m, 1H),7.62 (d, 1H), 7.92 (d, 1H) 8.26 (s, 1H), 10.14 (s, 1H), 10.22 (s, 1H);Mass Spectrum: M+H⁺ 549.

EXAMPLE 153-[5-(2-Chloropyrid-4-ylcarbonylamino)-2-methylphenyl]-6-(4-methylhomopiperazin-1-yl)-3,4-dihydroquinazolin-4-one

Using an analogous procedure to that described in Example 5,3-(5-amino-2-methylphenyl)-6-(4-methylhomopiperazin-1-yl)-3,4-dihydroquinazolin-4-onewas reacted with 2-chloropyridine-4-carbonyl chloride to give the titlecompound; NMR Spectrum: (DMSOd₆) 1.84–1.96 (m, 2H), 2.06 (s, 3H), 2.29(s, 3H), 2.42–2.49 (m, 2H), 2.62–2.68 (m, 2H), 3.53 (t, 2H), 3.58–3.64(m, 2H), 7.22 (d, 1H), 7.34 (m, 1H), 7.44 (m, 1H), 7.58 (d, 1H),7.73–7.78 (m, 2H), 7.82–7.86 (m, 1H), 7.96–7.98 (m, 2H), 8.50–8.62 (m,1H), 10.68 (s, 1H); Mass Spectrum: M+H⁺ 503 & 505.

The 3-(5-amino-2-methylphenyl)-6-(4-methylhomopiperazin-1-yl)3,4-dihydroquinazolin-4-one used as astarting material was prepared as follows:

A mixture of N-(2-methyl-5-nitrophenyl)-5-chloro-2-nitrobenzamide (5 g),N-methylhomopiperazine (9.28 ml) and DMSO (4 ml) was stirred and heatedto 80° C. for 4 hours. The reaction mixture was cooled to ambienttemperature and poured into water. The resultant precipitate wasisolated, washed with water and with diethyl ether and dried undervacuum at 40° C. There was thus obtainedN-(2-methyl-5-nitrophenyl)-5-(4-methylhomopiperazin-1-yl)-2-nitrobenzamide(5.42 g); NMR Spectrum: (DMSOd₆) 1.82–1.96 (m, 2H), 2.26 (s, 3H), 2.38(s, 3H), 2.42–2.52 (m, 2H), 2.61–2.65 (m, 2H), 3.59–3.63 (m, 2H),3.67–3.71 (m, 2H), 6.84–6.93 (m, 2H), 7.52 (d, 1H), 7.98 (d, 1H), 8.05(d, 1H), 8.55 (s, 1H), 10.13 (s, 1H); Mass Spectrum: M+H⁺ 414.

A mixture of the material so obtained, 10% palladium-on-carbon catalyst(0.54 g) and methanol (150 ml) was stirred under an atmosphere ofhydrogen gas until hydrogen uptake ceased. The catalyst was filtered offand the filtrate was evaporated. There was thus obtainedN-(5-amino-2-methylphenyl)-2-amino-5-(4-methylhomopiperazin-1-yl)benzamide(3.64 g); NMR Spectrum: (DMSOd₆) 1.8–1.92 (m, 2H), 2.04 (s, 3H), 2.25(s, 3H), 2.42–2.48 (m, 2H), 2.57–2.60 (m, 2H), 3.34–3.39 (m, 2H),3.4–3.45 (m, 2H), 4.85 (s, 2H), 5.46 (s, 2H), 6.37 (d, 1H), 6.62–6.74(m, 3H), 6.84 (d, 1H), 6.94 (s, 1H), 9.46 (d, 1H); Mass Spectrum: M+H⁺354.

A mixture of the material so obtained, triethyl orthoformate (3.41 ml),glacial acetic acid (0.3 ml) and ethanol (75 ml) was stirred and heatedto 70° C. for 16 hours. A 1N aqueous hydrochloric acid solution (20.6ml) was added and the mixture was stirred at 60° C. for 3 hours. Theresultant mixture was evaporated. The residue was dissolved in water,basified by the addition of sodium bicarbonate and extracted withmethylene chloride. The organic extract was evaporated to give3-(5-amino-2-methylphenyl)-6-(4-methylhomopiperazin-1-yl)-3,4-dihydroquinazolin-4-one(3.78 g); NMR Spectrum: (DMSOd₆) 1.86 (s, 3H), 1.89–1.92 (m, 2H), 2.24(s, 3H), 2.44–2.49 (m, 2H), 2.6–2.63 (m, 2H), 3.49–3.53 (m, 2H),3.58–3.62 (m, 2H), 5.14 (s, 2H), 6.46 (s, 1H), 6.6 (d, 1H), 7.01 (d,1H), 7.22 (s, 1H), 7.32 (d, 1H), 7.55 (d, 1H), 7.86 (s, 1H); MassSpectrum: M+H⁺ 364.

EXAMPLE 163-[5-(3,5-Difluorobenzamido)-2-methlphenyl]-6-(4-methylhomopiperazin-1-yl)-3,4-dihydroquinazolin-4-one

Using an analogous procedure to that described in Example 5,3-(5-amino-2-methylphenyl)-6-(4-methylhomopiperazin-1-yl)-3,4-dihydroquinazolin-4-onewas reacted with 35-difluorobenzoyl chloride to give the title compound;NMR Spectrum: (DMSOd₆) 1.84–1.96 (m, 2H), 2.05 (s, 3H), 2.25 (s, 3H),2.42–2.5 (m, 2H), 2.62–2.64 (m, 2H), 3.53 (t, 2H), 3.58–3.64 (m, 2H),7.24 (d, 1H), 7.38 (m, 1H), 7.40–7.44 (m, 1H), 7.48–7.54 (m, 1H), 7.58(d, 1H), 7.64–7.67 (m, 2H), 7.75–7.78 (m, 2H), 7.96 (s, 1H), 10.49.(s,1H); Mass Spectrum: M+H⁺ 504.

EXAMPLE 17

Using an analogous procedure to that described in Example 10, theappropriate 3-(5-amino-2-methylphenyl)-3,4-dihydroquinazolin-4-one wasreacted with the appropriate carboxylic acid to give the compoundsdescribed in Table VIII.

TABLE VIII

No. (R¹)_(m) Q Note 1 6-(4-methylpiperazin-1-yl) 1-fluorenyl a 26-(4-methylpiperazin-1-yl) 3,4-methylenedioxyphenyl b 36-(4-methylpiperazin-1-yl) 3,4-trimethylenedioxyphenyl c 46-(4-methylpiperazin-1-yl) 2,3-dihydrobenzofuran-7-yl d 56-(4-methylpiperazin-1-yl) 2-methyl-2,3-dihydrobenzo- e furan-7-yl 66-(4-methylpiperazin-1-yl) 2,2-dimethylchroman-6-yl f 76-(4-methylhomopiperazin- dibenzofuran-4-yl g 1-yl) 86-(4-methylhomopiperazin- 1-fluorenyl h 1-yl) 96-(4-methylpiperazin-1-yl) 5-(3-chlorophenyl)furan-2-yl i 106-(4-methylpiperazin-1-yl) 5-(4-chlorophenyl)furan-2-yl j 116-(4-methylpiperazin-1-yl) 5-(4-chlorophenyl)thien-2-yl k 126-(4-methylpiperazin-1-yl) 4-(4-chlorophenyl)thien-2-yl l 136-(4-methylpiperazin-1-yl) 4-(4-methoxyphenyl)thien- m 2-yl 146-(4-methylpiperazin-1-yl) 3-phenylisothiazol-5-yl n 158-(4-methylpiperazin-1-yl) dibenzofuran-4-yl o 168-(4-methylpiperazin-1-yl) 1-fluorenyl p 17 6-piperazin-1-yl 1-fluorenylq 18 6-piperazin-1-yl dibenzofuran-4-yl rNotesa) The product gave the following data: NMR Spectrum: (DMSOd₆) 2.05 (s,3H), 2.23 (s, 3H), 2.47–2.5 (m, 4H), 3.2–3.3 (m, 4H), 4.18 (s, 2H),7.3–7.48 (m, 4H), 7.5–7.63 (m, 4H), 7.75 (d, 1H), 7.8 (d, 1H), 7.87 (s,1H), 7.95 (d, 1H), 8.08–8.11 (m, 2H), 10.49 (s, 1H); Mass Spectrum: M−H⁻542.b) The product gave the following data: NMR Spectrum: (DMSOd₆) 2.05 (s,3H), 2.25 (s, 3H), 2.50 (m, 4H), 3.26 (m, 4H), 6.12 (s, 2H), 7.06 (d,1H), 7.41 (d, 1H), 7.49 (d, 2H), 7.58 (m, 1H), 7.65 (d, 2H), 7.88 (m,2H), 8.08 (s, 1H), 10.23 (s, 1H); Mass Spectrum: M+H⁺ 498.c) The product gave the following data: NMR Spectrum: (DMSOd₆) 2.05 (s,3H), 2.15 (m, 2H), 2.25 (s, 3H), 2.5–3.35 (m, 8H), 4.2 (m, 4H), 7.6 (d,1H), 7.4 (d, 1H), 7.48 (s, 1H), 7.55–7.65 (m, 4H), 7.76–7.85 (m, 2H),8.1 (s, 1H), 10.26 (s, 1H); Mass Spectrum: M+H⁺ 526.d) The product gave the following data: NMR Spectrum: (DMSOd₆) 2.05 (s,3H), 2.3 (s, 3H), 2.55 (m, 4H), 3.25 (m, 2H), 3.3 (m, 4H), 4.75 (t, 2H),6.98 (m, 1H), 7.39–7.49 (m, 3H), 7.58–7.65 (m, 3H), 7.8 (n, 2H), 8.1 (s,1H), 9.9 (s, 1H); Mass Spectrum: M+H⁺ 496.e) The 2-methyl-2,3-dihydrobenzofuran-7-carboxylic acid, used as astarting material, was obtained as described in Monatschefte fur Chemie.1990, 121, 883–891. The product gave the following data: NMR Spectrum:(DMSOd₆) 1.50 (m, 3H), 2.05 (s, 3H), 2.25 (s, 3H), 2.55 (m, 4H), 3.28(m, 4H), 3.39 (m, 2H), 5.12 (m, 1H); 6.98 (s, 1H), 7.41 (d, 2H), 7.49(s, 1H), 7.61 (m, 3H), 7.8 (m, 2H), 8.1 (s, 1H), 9.87 (s, 1H); MassSpectrum: M+H⁺ 510.f) The 2,2-dimethylchroman-6-carboxylic acid, used as a startingmaterial, was obtained as described in Tetrahedron, 1982, 38, 3673–3677.The product gave the following data: NMR Spectrum: (DMSOd₆) 1.30 (m,6H), 1.79 (m, 2H), 2.05 (s, 3H), 2.25 (s, 3H), 2.5 (m, 4H), 2.8 (m, 2H),3.3 (m, 4H), 6.8 (d, 1H), 7.38 (m, 1H), 7.46 (m, 1H), 7.62 (m, 2H),7.69–7.98 (m, 4H), 8.09 (s, 1H), 10.18 (s, 1H); Mass Spectrum: M+H⁺ 538.g) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.84–1.94(m, 2H), 2.07 (s, 3H), 2.25 (s, 3H), 2.42–2.5 (m, 2H), 2.62–2.66 (m,2H), 3.53 (t, 2H), 3.58–3.64 (m, 2H), 7.26 (s, 1H), 7.38 (d, 1H),7.4–7.5 (m, 2H), 7.51–7.61 (m, 3H), 7.78–7.86 (m, 4H), 8.01 (s, 1H),7.92–7.99 (m, 2H), 8.22 (d, 1H), 8.38 (d, 1H), 10.59 (s, 1H); MassSpectrum: M+H⁺ 558.h) The product gave the following data: NMR Spectrum: (DMSOd₆) 1.86–1.98(m, 2H), 2.06 (s, 3H), 2.25 (s, 3H), 2.42–2.5 (m, 2H), 2.62–2.66 (m,2H), 3.53 (t, 2H), 3.58–3.64 (m, 2H), 4.12 (s, 2H), 7.24 (s, 1H),7.32–7.43 (m, 4H), 7.52–7.61 (m, 3H), 7.72 (d, 1H), 7.8 (d, 1H), 7.85(s, 1H), 7.92–7.99 (m, 2H), 8.18 (d, 1H), 10.49 (s, 1H); Mass Spectrum:M+H⁺ 556.i) The 5-(3-chlorophenyl)furan-2-carboxylic acid, used as a startingmaterial, was obtained as described in Chem. Pharm. Bull., 1981, 29,2420–2430. The product gave the following data: NMR Spectrum: (DMSOd₆)2.05 (s, 3H), 2.22 (s, 3H), 2.47–2.5 (m, 4H), 3.25–3.35 (m, 4H), 7.28(d, 1H), 7.38–7.48 (m, 5H), 7.62 (s, 2H), 7.76 (s, 1H), 7.84 (m, 1H),7.9 (d, 1H), 8.08 (s, 2H), 10.38 (s, 1H); Mass Spectrum: M+H⁺ 554 & 556.j) The 5-(4-chlorophenyl)furan-2-carboxylic acid, used as a startingmaterial, was obtained using analogous procedures to those described inChem. Pharm. Bull., 1981, 29, 2420–2430. The product gave the followingdata: NMR Spectrum: (DMSOd₆) 2.05 (s, 3H), 2.22 (s, 3H), 2.47–2.5 (m,4H), 3.2–3.3 (m, 4H), 7.2 (d, 1H), 7.39–7.48 (m, 3H), 7.54 (d, 2H), 7.63(s, 2H), 7.75 (s, 1H), 7.84 (m, 1H), 7.98 (m, 2H), 8.08 (s, 1H), 10.34(s, 1H); Mass Spectrum: M+H⁺ 554 & 556.k) The product gave the following data: NMR Spectrum: (DMSOd₆) 2.04 (s,3H), 2.46 (s, 3H), 2.47–2.5 (m, 4H), 3.2–3.3 (m, 4H), 7.41 (d, 1H),7.48–7.51 (m, 3H), 7.6–7.65 (m, 3H), 7.73–7.8 (m, 4H), 8.01 (d, 1H),8.07 (s, 1H), 10.5 (s, 1H); Mass Spectrum: M+H⁺ 570 & 572.l) The product gave the following data: NMR Spectrum: (DMSOd₆) 2.05 (s,3H), 2.22 (s, 3H), 2.47–2.5 (m, 4H), 3.2–3.3 (m, 4H), 7.38–7.53 (m, 4H),7.61–7.65 (m, 2H), 7.72–7.8 (m, 4H), 8.08 (s, 1H), 8.22 (s, 1H), 8.47(s, 1H), 10.5 (s, 1H); Mass Spectrum; M+H⁺ 570 & 572.m) The product gave the following data: NMR Spectrum: (DMSOd₆) 2.05 (s,3H), 2.23 (s, 3H), 2.47–2.5 (m, 4H), 3.2–3.3 (m, 4H), 3.7 (s, 3H), 7.01(d, 2H), 7.43 (d, 1H), 7.48 (s, 1H), 7.6–7.66 (m, 4H), 7.74–7.8 (m, 2H),8.02 (s, 1H), 8.08 (s, 1H), 8.4 (s, 1H), 10.41 (s, 1H); Mass Spectrum:M+H⁺ 566.n) The 3-phenyl)isothiazole-5-carboxylic acid, used as a startingmaterial, was obtained as described in Helv. Chim. Acta, 1966, 49,2466–2469. The product gave the following data: NMR Spectrum: (DMSOd₆)2.03 (s, 3H), 2.22 (s, 3H), 2.47–2.5 (m, 4H), 3.25–3.35 (m, 4H), 7.35(d, 1H), 7.44–7.52 (m, 5H), 7.62 (s, 1H), 7.64–7.73 (m, 2H), 7.98 (d,2H), 8.06 (s, 1H), 8.4 (s, 1H), 10.38 (s, 1H); Mass Spectrum: M+H⁺ 537.o) The product gave the following data: NMR Spectrum: (DMSOd₆) 2.05 (s,3H), 2.2 (s, 4H), 7.3–7.35 (m, 1H), 7.4–7.6 (m, 51H), 7.75–7.9 (m, 5H),8.2 (d, 1H), 8.3–8.4 (m, 2H), 10.6 (s, 1H); Mass Spectrum: M+H⁺ 544.p) The product gave the following data NMR Spectrum: (DMSOd₆) 2.05 (s,3H), 2.3 (s, 3H), 2.5–2.65 (m, 4H), 4.18 (s, 2H), 7.3–7.65 (m, 7H),7.7–7.8 (m, 3H), 7.9 (s, 1H), 7.95 (d, 1H), 8.1 (d, 1H), 8.3 (s, 1H),10.5 (s, 1H); Mass Spectrum: M+H⁺ 542.q)3-(5-Amino-2-methylphenyl)-6-(4-tert-butoxycarbonylpiperazin-1-yl)3.4-dihydroquinazolin-4-onewas used as a starting material. The initial reaction product was3-[5-fluoren-1-ylcarbonylamino-2-methylphenyl]-6-(4-tert-butoxycarbonylpiperazin-1-yl)-3,4-dihydroquinazolin-4-onewhich was treated with a saturated solution of hydrogen chloride inethanol to cleave the tert-butoxycarbonyl protecting group. Theresultant product gave the following data: NMR Spectrum: (DMSOd₆) 2.07(s, 3H), 3.26 (m, 4H), 3.5 (m, 4H), 4.18 (s, 2H), 7.32–7.5 (m, 4H),7.55–7.63 (m, 3H), 7.69–7.81 (m, 4H), 7.91–8.0 (m, 3H), 8.11 (s, 1H),8.87 (s, 1H); Mass Spectrum: M+H⁺ 528.

The3-(5-amino-2-methylphenyl)-6-(4-tert-butoxycarbonylpiperazin-1-yl)-3,4-dihydroquinazolin-4-oneused as a starting material was prepared as follows:

A mixture of N-(2-methyl-5-nitrophenyl)-5-chloro-2-nitrobenzamide (5.02g), piperazine (5.13 g) and DMSO (15 ml) was stirred and heated to 100°C. for 2 hours. The mixture was cooled to ambient temperature and pouredinto water. The resultant solid was isolated, washed in turn with waterand diethyl ether and dried under vacuum at 55° C. There was thusobtained N-(2-methyl-5-nitrophenyl)-2-nitro-5-piperazin-1-ylbenzamide(4.88 g); NMR Spectrum: (DMSOd₆) 2.38 (s, 3 H), 2.8 (m, 4H), 3.43 (m,4H), 7.04 (m, 1H), 7.14 (d, 1H), 7.52 (d, 1H), 8.01 (m, 1H), 8.06 (d,1H), 8.53 (d, 1H), 10.14 (s, 1H); Mass Spectrum: M+H⁺ 386.

2-(tert-Butoxycarbonyloxyimino)phenylacetonitrile (2.55 g) was added toa mixture ofN-(2-methyl-5-nitrophenyl)-2-nitro-5-piperazin-1-ylbenzamide (2.5 g),triethylamine (1.7 ml), water (30 ml) and 1,4-dioxane (30 ml) and thereaction mixture was stirred at ambient temperature for 16 hours. Themixture was diluted with water and the resultant solid was isolated andwashed in turn with water and diethyl ether. There was thus obtainedN-(2-methyl-5-nitrophenyl)-5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-nitrobenzamide(2.85 g); NMR Spectrum: (CDCl₃) 1.48 (s, 9H), 2.37 (s, 3H), 3.48 (m,4H), 3.61 (m, 4H), 6.77 (m, 1H), 6.87 (m, 1H), 7.33 (d, 1H), 7.56 (s,1H), 7.95 (m, 1H), 8.04 (d, 1H), 8.68 (s, 1H); Mass Spectrum: M+H⁺ 484.

The material so obtained was hydrogenated in the presence of 10%palladium-on-carbon catalyst using an analogous procedure to thatdescribed in the third paragraph of the portion of Example 5 which isconcerned with the preparation of starting materials. There was thusobtainedN-(5-amino-2-methylphenyl)-2-amino-5-(4-tert-butoxycarbonylpiperazin-1-yl)benzamidein 96% yield; NMR Spectrum: (CDCl₃) 1.5 (s, 9H), 2.21 (s, 3H) 3.0 (m,4H), 3.6 (m, 4H), 3.65 (s, 2H), 4.98 (s, 2H), 6.47 (m, 1H), 6.73 (d,1H), 7.01 (m, 2H), 7.11 (d, 1H), 7.41 (d, 1H), 7.8 (s, 1H); MassSpectrum: M+H⁺ 426.

A mixture of the material so obtained (2.12 g), triethyl orthoformate(1.7 ml), glacial acetic acid (0.07 ml) and ethanol (50 ml) was stirredand heated to 70° C. for 16 hours. A sodium hydroxide solution (1M, 5.0ml) was added and the mixture was stirred and heated to 60° C. for 16hours. A further portion of sodium hydroxide solution (1 M, 2.5 ml) wasadded and the mixture was again heated to 60° C. for 16 hours. Theresultant mixture was cooled to ambient temperature and evaporated. Theresidue was dissolved in water and extracted with methylene chloride.The organic phase was dried and evaporated. The material so obtained waspurified by column chromatography on silica using a 20:1 mixture ofmethylene chloride and methanol. There was thus obtained3-(5-amino-2-methylphenyl)-6-(4-tert-butoxycarbonylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one(1.51 g); NMR Spectrum: (CDCl₃) 1.5 (s, 9H), 2.06 (s, 3H), 3.27 (m, 4H),3.62 (m, 4H), 3.72 (s, 2H), 6.58 (d, 1H), 6.74 (m, 1H), 7.15 (d, 1H),7.44 (m, 1H), 7.68 (m, 2H), 7.86 (s, 1H); Mass Spectrum: M+H⁺ 436.

r)3-(5-Amino-2-methylphenyl)-6-(4-tert-butoxycarbonylpiperazin-1-yl)-3,4-dihydroquinazolin-4-onewas used as a starting material. The initial reaction product was3-[-dibenzofuran-4-ylcarbonylamino-2-methylphenyl]-6-(4-tert-butoxycarbonylpiperazin-1-yl)-3,4-dihydroquinazolin-4-onewhich was treated with a saturated solution of hydrogen chloride inethanol to cleave the tert-butoxycarbonyl protecting group. Theresultant product gave the following data: NMR Spectrum: (DMSOd₆) 2.07(s, 3H), 3.29 (m, 4H), 3.5 (m, 4H), 7.42–7.6 (m, 6H), 7.67 (m, 1H),7.8–7.9 (m, 4H), 7.95 (s, 1H), 8.20–8.27 (m, 2H), 8.36 (d, 1H), 8.85 (s,1H); Mass Spectrum: M+H⁺ 530.

EXAMPLE 183-12-Fluoro-5-(3-fluoro-5-morpholinobenzamido)phenyl-6-(4-methylpiperazin-1-yl)3.4-dihydroquinazolin-4-one

Triethyl orthoformate (0.12, ml) was added to a stirred mixture of N-[2-fluoro-5-(3-fluoro-5-morpholinobenzamido)phenyl]-2-amino-5-(4-methylpiperazinyl)benzamide (0.31 g), glacial acetic acid(0.016 ml) and ethanol (4 ml) and the resultant mixture was heated to76° C. for 18 hours. The mixture was evaporated and the residue waspartitioned between methylene chloride and a saturated aqueous solutionof sodium bicarbonate. The organic solution was washed with water andwith a saturated aqueous sodium chloride solution, dried (MgSO₄) andevaporated. The residue was purified by column chromatography on silicausing increasingly polar mixtures of methylene chloride and methanol aseluent. There was thus obtained the title compound (0.119 g); NMRSpectrum: (DMSOd₆) 2.23 (s, 3H), 3.22 (m, 4H), 3.72 (m, 4H), 6.99 (d,1H), 7.12 (d, 1H), 7.29 (s, 1H), 7.47 (m, 2H), 7.63 (s, 1H), 7.89 (m,1H), 7.97 (m, 1H), 8.18 (s, 1H), 10.44 (s, 1H); Mass Spectrum: M+H⁺ 561.

TheN-[2-fluoro-5-(3-fluoro-5-morpholinobenzamido)phenyl]-2-amino-5-(4-methylpiperazin-1-yl)benzamideused as a starting material was prepared as follows:

Oxalyl chloride (0.55 g) was added dropwise to a stirred mixture of3-fluoro-5-morpholinobenzoic acid (6.36 g), DMF (a few drops) andmethylene chloride (200 ml) which had been cooled to 0° C. The mixturewas allowed to warm to ambient temperature and was stirred for 4 hours.The mixture was evaporated. The residue was dissolved in methylenechloride (100 ml) and was added dropwise to a stirred mixture of4-fluoro-3-nitroaniline (4.05 g), triethylamine (12.0 ml) and methylenechloride (100 ml). The resultant mixture was stirred at ambienttemperature for 20 hours. The mixture was evaporated and the residue waspartitioned between methylene chloride and water. The organic phase waswashed with a saturated aqueous sodium chloride solution, dried (MgSO₄)and evaporated. There was thus obtainedN-(4-fluoro-3-nitrophenyl)-3-fluoro-5-morpholinobenzamide (7.06 g); NMRSpectrum: (DMSOd₆) 3.24 (m, 4H), 3.73 (m, 4H), 7.0 (m, 1H), 7.13 (d,1H), 7.3 (s, 1H), 7.58 (t, 1H), 8.11 (m, 1H), 8.63 (m, 1H), 10.56 (s,1H); Mass Spectrum: (M−H)⁻ 362.

A mixture of a portion (4.34 g) of the material so obtained, 30%palladium-on-carbon (0.68 g) and methanol (500 ml) was stirred under anatmosphere of hydrogen gas. After cessation of hydrogen uptake, thecatalyst was removed by filtration and the filtrate was evaporated.There was thus obtainedN-(3-amino-4-fluorophenyl)-3-fluoro-5-morpholinobenzamide (3.49 g); NMRSpectrum: (DMSOd₆) 3.22 (m, 4H), 3.75 (m, 4H), 5.12 (s, 2H), 6.81 (m,1H), 6.89–6.96 (m, 2H), 7.08 (d, 1H), 7.24 (m, 2H), 9.92 (s, 1H) MassSpectrum: M+H⁺ 334.

Diisopropylamine (3.13 ml) was added to a mixture ofN-(3-amino-4-fluorophenyl)3-fluoro-5-morpholinobenzamide (1.99 g),5-chloro-2-nitrobenzoic acid (1.45 g)2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate(V) (2.74 g) in DMF (12 ml) and the reaction mixturewas stirred at ambient temperature for 18 hours. The mixture was pouredinto water and the resultant precipitate was isolated, washed with waterand dried under vacuum at 55° C. There was thus obtainedN-[2-fluoro-5-(3-fluoro-5-morpholinobenzamido)phenyl]-5-chloro-2-nitrobenzamide(1.64 g); NMR Spectrum: (DMSOd₆) 3.22 (m, 4H), 3.74 (m, 4H), 6.97 (d,1H), 7.15 (d, 1H), 7.25–7.32 (m, 2H), 7.66 (m, 1H), 7.82 (m, 2H), 7.88(s, 1H), 8.18 (d, 1H), 8.34 (m, 1H), 10.32 (s, 1H), 10.58 (s, 1H); MassSpectrum: M+H⁺ 517 and 519.

A mixture of a portion (0.55 g) of the material so obtained andN-methylpiperazine (2 ml) was stirred and heated to 80° C. for 18 hours.The reaction mixture was cooled to ambient temperature and poured intowater. The resultant precipitate was isolated, washed with water anddried under vacuum at 55° C. There was thus obtainedN-[2-fluoro-5-(3-fluoro-5-morpholinobenzamido)phenyl]-5-(4-methylpiperazin-1-yl-2-nitrobenzamide(0.55 g); NMR Spectrum: (DMSOd₆) 2.2 (s, 3H), 2.41 (m, 3H), 3.22 (m,4H), 3.48 (m, 4H), 3.72 (m, 4H), 6.93 (m, 2H), 7.07 (m, 1H), 7.16 (d,1H), 7.25 (t, 1H), 7.32 (s, 1H), 7.63 (m, 1H), 8.14 (d, 1H), 8.36 (m,1H), 10.26 (s, 1H), 10.3 (s, 1H); Mass Spectrum: M+H⁺ 581.

A mixture of the material so obtained, 30% palladium-on-carbon (0.075 g)and ethanol (500 ml) was stirred under an atmosphere of hydrogen gas.After cessation of hydrogen uptake, the catalyst was removed byfiltration and the filtrate was evaporated. There was thus obtainedN-[2-fluoro-5-(3-fluoro-5-morpholinobenzamido)pheny[]-2-amino-5-(4-methylpiperazin-1-yl)benzamide(0.52 g); NMR Spectrum: (DMSOd₆) 2.22 (s, 3H), 2.44 (m, 4H), 2.98 (m,4H), 3.21 (m, 4H), 3.72 (m, 4H), 5.93 (br s, 1H), 6.69 (d, 1H) 6.94–7.01(m, 2H), 7.12 (d, 1H), 7.2–7.3 (m, 3H), 7.59 (m, 1H), 7.97 (m, 1H),10.24 (s, 1H); Mass Spectrum: M+H⁺ 551.

EXAMPLE 193–12-Fluoro-5-(3-fluoro-5-morpholinobenzamido)phenyl]-6-(4-methylhomopiperazin-1-yl)-3,4-dihydroquinazolin-4-one

Using an analogous procedure to that described in Example 1 8,N-[2-fluoro-5-(3-fluoro-5-morpholinobenzamido)phenyl]-2-amino-5-(4-methylhomopiperazin-1-yl)benzamidewas reacted with triethyl orthoformate to give the title compound in 63%yield; NMR Spectrum: (DMSOd₆) 1.92 (m, 2H), 2.25 (s, 3H), 2.46 (m, 2H),2.64 (m, 2H), 3.21 (t, 4H), 3.53 (t, 2H), 3.6 (m, 2H), 3.72 (t, 4H),6.99 (d, 1H), 7.12 (d, 1H), 7.23 (m, 1H), 7.3 (s, 1H), 7.36 (m, 1H),7.48 (t, 1H), 7.58 (d, 1H), 7.87 (m, 1H), 7.96 (m, 1H), 8.06 (s, 1H),10.43 (s, 1H); Mass Spectrum: M+H⁺ 575.

TheN-[2-fluoro-5-(3-fluoro-5-morpholinobenzamido)phenyl]-2-amino-5-(4-methylhomopiperazin-1-yl)benzamideused as a starting material was prepared as follows:

A mixture ofN-[2-fluoro-5-(3-fluoro-5-morpholinobenzamido)phenyl]-5-chloro-2-nitrobenzamide(0.55 g) and N-methylhomopiperazine (2 ml) was stirred and heated to 80°C. for 18 hours. The reaction mixture was cooled to ambient temperatureand poured into water. The resultant precipitate was isolated, washedwith water and dried under vacuum at 55° C. There was thus obtainedN-[2-fluoro-5-(3-fluoro-5-morpholinobenzamido)phenyl]-5-(4-methylhomopiperazin-1-yl-2-nitrobenzamide(0.58 g); NMR Spectrum: (DMSOd₆) 1.89 (m, 2H), 2.25 (s, 3H), 2.44 (m,2H), 2.63 (m, 2H), 3.22 (t, 4H), 3.59 (t, 2H), 3.66 (m, 2H), 3.74 (t,4H), 6.72 (d, 1H), 6.87, (m, 1H), 6.97 (d, 1H), 7.16 (d, 1H), 7.23 (t,1H), 7.31 (s, 1H), 7.63 (m, 1H), 8.02 (d, 1H), 8.34 (m, 1H), 10.3 (s,1H); Mass Spectrum: M+H⁺ 595.

A mixture of the material so obtained, 30% palladium-on-carbon (0.08 g)and ethanol (500 ml) was stirred under an atmosphere of hydrogen gas.After cessation of hydrogen uptake, the catalyst was removed byfiltration and the filtrate was evaporated. There was thus obtainedN-[2-fluoro-5-(3-fluoro-5-morpholinobenzamido)phenyl]-2-amino-5-(4-methylhomopiperazin-1-yl)benzamide(0.48 g); NMR Spectrum: (DMSOd₆) 1.86 (m, 2H), 2.24 (s, 3H), 2.44 (m,2H), 2.59 (m, 2H), 3.22 (t, 4H), 3.38 (t, 2H), 3.43 (m, 2H), 3.72 (t,4H), 6.68 (d, 1H), 6.76 (m, 1H), 6.98 (m, 2H), 7.12 (m, 1H), 7.22–7.31(m, 2H), 7.58 (m, 1H), 8.08 (m, 1H), 10.25 (br s, 1H); Mass Spectrum:M+H⁺ 565.

EXAMPLE 20 Pharmaceutical Compositions

The following illustrate representative pharmaceutical dosage forms ofthe invention as defined herein (the active ingredient being termed“Compound X”), for therapeutic or prophylactic use in humans:

(a) Tablet I mg/tablet Compound X 100 Lactose Ph. Eur 182.75Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25Magnesium stearate 3.0 (b) Tablet II mg/tablet Compound X 50 Lactose Ph.Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0Polyvinylpyrrolidone (5% w/v paste) 2.25 Magnesium stearate 3.0 (c)Tablet III mg/tablet Compound X 1.0 Lactose Ph. Eur 93.25 Croscarmellosesodium 4.0 Maize starch paste (5% w/v paste) 0.75 Magnesium stearate 1.0(d) Capsule mg/capsule Compound X 10 Lactose Ph. Eur 488.5 Magnesium 1.5(e) Injection I (50 mg/ml) Compound X 5.0% w/v 1M Sodium hydroxidesolution 15.0% v/v 0.1M Hydrochloric acid (to adjust pH to 7.6)Polyethylene glycol 400 4.5% w/v Water for injection to 100% (f)Injection II (10 mg/ml) Compound X 1.0% w/v Sodium phosphate BP 3.6% w/v0.1M Sodium hydroxide solution 15.0% v/v Water for injection to 100% (g)Injection III (1 mg/ml, buffered to pH6) Compound X 0.1% w/v Sodiumphosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol 4003.5% w/v Water for injection to 100% (h) Aerosol I mg/ml Compound X 10.0Sorbitan trioleate 13.5 Trichlorofluoromethane 910.0Dichlorodifluoromethane 490.0 (i) Aerosol II mg/ml Compound X 0.2Sorbitan trioleate 0.27 Trichlorofluoromethane 70.0Dichlorodifluoromethane 280.0 Dichlorotetrafluoroethane 1094.0 (j)Aerosol III mg/ml Compound X 2.5 Sorbitan trioleate 3.38Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6 (k) Aerosol IV mg/ml Compound X 2.5 Soyalecithin 2.7 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6 (l) Ointment ml Compound X 40 mg Ethanol300 μl Water 300 μl 1-Dodecylazacycloheptan-2-one 50 μl Propylene glycolto 1 ml Note The above formulations may be obtained by conventionalprocedures well known in the pharmaceutical art. The tablets (a)–(c) maybe enteric coated by conventional means, for example to provide acoating of cellulose acetate phthalate. The aerosol formulations (h)–(k)may be used in conjunction with standard, metered dose aerosoldispensers, and the suspending agents sorbitan trioleate and soyalecithin may be replaced by an alternative suspending agent such assorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerololeate or oleic acid.

1. An amide derivative of the Formula Ia

wherein X is —NHCO— or —CONH–; m is 1, 2 or 3; at least one R¹ is apiperazinyl group and any other R¹ that is present is selected fromhydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino,carboxy, carbamoyl, formyl, (1–6C)alkyl, (2–6C)alkenyl, (2–6C)alkynyl,(1–6C)alkoxy, (1–6C)alkylthio, (1–6C)alkylsulphinyl,(1–6C)alkylsulphonyl, (1–6C)alkylamino, di-[(1–6C)alkyl]amino,(1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, (2–6C)alkanoyloxy,(1–6C)alkanoylamino, N-(1–6C)alkyl(1–6C)alkanoylamino,N-(1–6C)alkylsulphamoyl, N,N-di-[(1–6C)alkyl]sulphamoyl,(1–6C)alkanesulphonylamino, N-(1–6C)alkyl-(1–6C)alkanesulphonylamino,halogeno-(1–6C)alkyl, hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl,cyano-(1–6C)alkyl, amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,di-[(1–6C)alkyl]amino-(1–6C)alkyl, carboxy-(1–6C)alkyl,(1–6C)alkoxycarbonyl-(1–6C)alkyl, carbamoyl-(1–6C)alkyl,N-(1–6C)alkylcarbamoyl-(1–6C)alkyl,N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkyl, halogeno-(2–6C)alkoxy,hydroxy-(2–6C)alkoxy, (1–6C)alkoxy-(2–6C)alkoxy, cyano-(1–6C)alkoxy,carboxy-(1–6C)alkoxy, (1–6C)alkoxycarbonyl-(1–6C)alkoxy,carbamoyl-(1–6C)alkoxy, N-(1–6C)alkylcarbamoyl-(1–6C)alkoxy,N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkoxy, amino-(2–6C)alkoxy,(1–6C)alkylamino-(2–6C)alkoxy, di-[(1–6C)alkyl]amino-(2–6C)alkoxy,halogeno-(2–6C)alkylamino, hydroxy-(2–6C)alkylamino,(1–6C)alkoxy-(2–6C)alkylamino, cyano-(1–6C)alkylamino,carboxy-(1–6C)alkylamino, (1–6C)alkoxycarbonyl-(1–6C)alkylamino,carbamoyl-(1–6C)alkylamino, N-(1–6C)alkylcarbamoyl-(1–6C)alkylamino,N,N-di-[(1–6C)alkyl]carbamoyl (1–6C)alkylamino, amino-(2–6C)alkylamino,(1–6C)alkylamino-(2–6C)alkylamino,di-[(1–6C)alkyl]amino-(2–6C)alkylamino,N-(1–6C)alkyl-halogeno-(1–6C)alkylamino,N-(1–6C)alkyl-hydroxy-(2–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkoxy-(2–6C)alkylamino,N-(1–6C)alkyl-cyano-(1–6C)alkylamino,N-(1–6C)alkyl-carboxy-(1–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkoxycarbonyl-(1–6C)alkylamino,N-(1–6C)alkyl-carbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-N-(1–6C)alkylcarbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-amino-(2–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkylamino-(2–6C)alkylamino,N-(1–6C)alkyl-di-[(1–6C)alkyl]amino-(2–6C)alkylamino,halogeno-(2–6C)alkanoylamino, hydroxy-(2–6C)alkanoylamino,(1–6C)alkoxy-(2–6C)alkanoylamino, cyano-(2–6C)alkanoylamino,carboxy-(2–6C)alkanoylamino, (1–6C)alkoxycarbonyl-(2–6C)alkanoylamino,carbamoyl-(2–6C)alkanoylamino,N-(1–6C)alkylcarbamoyl-(2–6C)alkanoylamino,N,N-di-[(1–6C)alkyl]carbamoyl(2–6C)alkanoylamino,amino-(2–6C)alkanoylamino, (1–6C)alkylamino-(2–6C)alkanoylamino,di-[(1–6C)alkyl]amino-(2–6C)alkanoylamino and (1–3C)alkylenedioxy, andwherein any of the R’ substituents defined hereinbefore which comprisesa CH₂ group which is attached to 2 carbon atoms or a CH₃ group which isattached to a carbon atom may optionally bear on each said CH₂ or CH₃group a substituent selected from hydroxy, amino, (1–6C)alkoxy,(1–6C)alkylamino and di-[(1–6C)alkyl]amino, and wherein any piperazinylgroup in a R¹ substituent may optionally bear 1 or 2 substituentsselected from hydroxy, halogeno, (1–6C)alkyl, (1–6C)alkoxy, carboxy,(1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, amino, (1–6C)alkylamino,di-[(1–6C)alkyl]amino, halogeno-(1–6C)alkyl, hydroxy-(1–6C)alkyl,(1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl, amino-(1–6C)alkyl,(1–6C)alkylamino-(1–6C)alkyl, di-[(1–6C)alkyl]amino-(1–6C)alkyl, aryland aryl-(1–6C)alkyl, and wherein any piperazinyl group in a R’substituent may optionally bear 1 or 2 oxo or thioxo substituents; n is0, 1 or 2; R² is hydroxy, halogeno, trifluoromethyl, cyano, mercapto,nitro, amino, carboxy, (1–6C)alkoxycarbonyl, (1–6C)alkyl, (2–6C)alkenyl,(2–6C)alkynyl, (1–6C)alkoxy, (1–6C)alkylamino or di-[(1–6C)alkyl]amino;R³ is hydrogen, halogeno, (1–6C)alkyl or (1–6C)alkoxy; q is 0, 1, 2, 3or 4; and Q is aryl, optionally substituted with 1, 2 or 3 substituentsselected from hydroxy, halogeno, trifluoromethyl, cyano, mercapto,nitro, amino, carboxy, carbamoyl, formyl, (1–6C)alkyl, (2–6C)alkenyl,(2–6C)alkynyl, (1–6C)alkoxy, (1–6C)alkylthio, (1–6C)alkylsulphinyl,(1–6C)alkylsulphonyl, (1–6C)alkylamino, di-[(1–6C)alkyl]amino,(1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, (2–6C)alkanoyloxy,(1–6C)alkanoylamino, N-(1–6C)alkyl-(1–6C)alkanoylamino,N-(1–6C)alkylsulphamoyl, N,N-di-[(1–6C)alkyl]sulphamoyl,(1–6C)alkanesulphonylamino, N-(1–6C)alkyl-(1–6C)alkanesulphonylamino,halogeno-(1–6C)alkyl, hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl,cyano-(1–6C)alkyl, amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,di-[(1–6C)alkyl]amino-(1–6C)alkyl, carboxy-(1–6C)alkyl,(1–6C)alkoxycarbonyl(1–6C)alkyl, carbamoyl-(1–6C)alkyl,N-(1–6C)alkylcarbamoyl-(1–6C)alkyl,N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkyl, halogeno-(2–6C)alkoxy,hydroxy-(2–6C)alkoxy, (1–6C)alkoxy-(2–6C)alkoxy, cyano-(1–6C)alkoxy,carboxy-(1–6C)alkoxy, (1–6C)alkoxycarbonyl-(1–6C)alkoxy,carbamoyl-(1–6C)alkoxy, N-(1–6C)alkylcarbamoyl-(1–6C)alkoxy,N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkoxy, amino-(2–6C)alkoxy,(1–6C)alkylamino-(2–6C)alkoxy, di-[(1–6C)alkyl]amino-(2–6C)alkoxy,halogeno-(2–6C)alkylamino, hydroxy-(2–6C)alkylamino,(1–6C)alkoxy-(2–6C)alkylamino, cyano-(1–6C)alkylamino,carboxy-(1–6C)alkylamino, (1–6C)alkoxycarbonyl-(1–6C)alkylamino,carbamoyl-(1–6C)alkylamino, N-(1–6C)alkylcarbamoyl-(1–6C)alkylamino,N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkylamino, amino-(2–6C)alkylamino,(1–6C)alkylamino-(2–6C)alkylamino,di-[(1–6C)alkyl]amino-(2–6C)alkylamino,N-(1–6C)alkyl-halogeno-(1–6C)alkylamino,N-(1–6C)alkyl-hydroxy-(2–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkoxy-(2–6C)alkylamino,N-(1–6C)alkyl-cyano-(1–6C)alkylamino,N-(1–6C)alkyl-carboxy-(1–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkoxycarbonyl-(1–6C)alkylamino,N-(1–6C)alkyl-carbamoyl(1–6C)alkylamino,N-(1–6C)alkyl-N-(1–6C)alkylcarbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-amino-(2–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkylamino(2–6C)alkylamino,N-(1–6C)alkyl-di-[(1–6C)alkyl]amino-(2–6C)alkylamino,halogeno-(2–6C)alkanoylamino, hydroxy-(2–6C)alkanoylamino,(1–6C)alkoxy-(2–6C)alkanoylamino, cyano-(2–6C)alkanoylamino,carboxy-(2–6C)alkanoylamino, (1–6C)alkoxycarbonyl-(2–6C)alkanoylamino,carbamoyl-(2–6C)alkanoylamino,N-(1–6C)alkylcarbamoyl-(2–6C)alkanoylamino,N,N-di-[(1–6C)alkyl]carbamoyl-(2–6C)alkanoylamino,amino-(2–6C)alkanoylamino, (1–6C)alkylamino-(2–6C)alkanoylamino,di-[(1–6C)alkyl]amino-2–6C)alkanoylamino, aryl, aryl-(1–6C)alkyl,aryl-(1–6C)alkoxy, aryloxy, arylamino, N-(1–6C)alkyl-arylamino,aryl-(1–6C)alkylamino, N-(1–6C)alkyl-aryl-(1–6C)alkylamino, aroylamino,arylsulphonylamino, N-arylsulphamoyl, aryl-(2–6C)alkanoylamino and(1–3C)alkylenedioxy, and wherein any of the substituents on Q definedhereinbefore which comprises a CH₂ group which is attached to 2 carbonatoms or a CH₃ group which is attached to a carbon atom may optionallybear on each said CH₂ or CH₃ group a substituent selected from hydroxy,amino, (1–6C)alkoxy, (1–6C)alkylamino and di-[(1–6C)alkyl]amino, andwherein any aryl group in a substituent on Q may optionally bear 1 or 2substituents selected from hydroxy, halogeno, (1–6C)alkyl, (1–6C)alkoxy,carboxy, (1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, amino, (1–6C)alkylamino,di-[(1–6C)alkyl]amino, halogeno-(1–6C)alkyl, hydroxy-(1–6C)alkyl,(1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl, amino-(1–6C)alkyl,(1–6C)alkylamino-(1–6C)alkyl, di-[(1–6C)alkyl]amino-(1–6C)alkyl, aryland aryl-(1–6C)alkyl; or a pharmaceutically-acceptable salt orin-vivo-cleavable ester formed on an available carboxy group thereof. 2.An amide derivative of the Formula Ib

wherein m is 1, 2 or 3; at least one R¹ is piperazinyl group and anyother R¹ group that is present is selected from hydroxy, halogeno,trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl,formyl, (1–6C)alkyl, (2–6C)alkenyl, (2–6C)alkynyl, (1–6C)alkoxy,(1–6C)alkylthio, (1–6C)alkylsulphinyl, (1–6C)alkylsulphonyl,(1–6C)alkylamino, di-[(l -6C)alkyl]amino, (1–6C)alkoxycarbonyl,N-(1–6C)alkylcarbamoyl, N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl,(2–6C)alkanoyloxy, (1–6C)alkanoylamino, N-(1–6C)alkylsulphamoyl,N,N-di-[(1–6C)alkyl]sulphamoyl, (1–6C)alkanesulphonylamino,N-(1–6C)alkyl(1–6C)alkanesulphonylamino, halogeno-(1–6C)alkyl,hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl,amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,di-[(1–6C)alkyl]amino-(1–6C)alkyl, carboxy-(1–6C)alkyl,(1–6C)alkoxycarbonyl-(1–6C)alkyl, carbamoyl-(1–6C)alkyl,N-(1–6C)alkylcarbamoyl(1–6C)alkyl, N,N-di-[(1–6C)alkyl]carbamoyl-(i-6C)alkyl, halogeno-(2–6C)alkoxy, hydroxy-(2–6C)alkoxy,(1–6C)alkoxy-(2–6C)alkoxy, cyano-(1–6C)alkoxy, carboxy-(1–6C)alkoxy,(1–6C)alkoxycarbonyl-(1–6C)alkoxy, carbamoyl-(1–6C)alkoxy,N-(1–6C)alkylcarbamoyl-(1–6C)alkoxy,N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkoxy, amino-(2–6C)alkoxy,(1–6C)alkylamino-(2–6C)alkoxy, di-[(1–6C)alkyl]amino(2–6C)alkoxy,halogeno-(2–6C)alkylamino, hydroxy-(2–6C)alkylamino,(1–6C)alkoxy-(2–6C)alkylamino, cyano-(1–6C)alkylamino,carboxy-(1–6C)alkylamino, (1–6C)alkoxycarbonyl-(1–6C)alkylamino,carbamoyl-(1–6C)alkylamino, N-(1–6C)alkylcarbamoyl-(1–6C)alkylamino,N,N-di-[(1–6C)alkyl]carbamoyl(1–6C)alkylamino, amino-(2–6C)alkylamino,(1–6C)alkylamino-(2–6C)alkylamino,di-[(1–6C)alkyl]amino-(2–6C)alkylamino,N-(1–6C)alkyl-halogeno-(1–6C)alkylamino,N-(1–6C)alkyl-hydroxy-(2–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkoxy(2–6C)alkylamino,N-(1–6C)alkyl-cyano-(1–6C)alkylamino,N-(1–6C)alkyl-carboxy(1–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkoxycarbonyl-(1–6C)alkylamino,N-(1–6C)alkyl-carbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-N-(1–6C)alkylcarbamoyl(1–6C)alkylamino,N-(1–6C)alkyl-N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-amino-(2–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkylamino(2–6C)alkylamino,N-(1–6C)alkyl-di-[(1–6C)alkyl]amino-(2–6C)alkylamino,halogeno-(2–6C)alkanoylamino, hydroxy-(2–6C)alkanoylamino,(1–6C)alkoxy(2–6C)alkanoylamino, cyano-(2–6C)alkanoylamino,carboxy-(2–6C)alkanoylamino, (1–6C)alkoxycarbonyl-(2–6C)alkanoylamino,carbamoyl-(2–6C)alkanoylamino,N-(1–6C)alkylcarbamoyl-(2–6C)alkanoylamino,N,N-di-[(1–6C)alkyl]carbamoyl(2–6C)alkanoylamino,amino-(2–6C)alkanoylamino, (1–6C)alkylamino(2–6C)alkanoylamino,di-[(1–6C)alkyl]amino-(2–6C)alkanoylamino and (1–3C)alkylenedioxy, andwherein any of the R’ substituents defined hereinbefore which comprisesa CH₂ group which is attached to 2 carbon atoms or a CH₃ group which isattached to a carbon atom may optionally bear on each said CH₂ or CH₃group a substituent elected from hydroxy, amino, (1–6C)alkoxy,(1–6C)alkylamino and di-[(l -6C)alkyl]amino, and wherein any piperazinylgroup in a R¹ substituent may optionally bear 1 or 2 substituentsselected from hydroxy, halogeno, (1–6C)alkyl, (1–6C)alkoxy, carboxy,(1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, amino, (1–6C)alkylamino,di-[(1–6C)alkyl]amino, halogeno-(1–6C)alkyl, hydroxy-(1–6C)alkyl,(1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl, amino-(1–6C)alkyl,(1–6C)alkylamino-(1–6C)alkyl, di-[(1–6C)alkyl]amino-(1–6C)alkyl, aryland aryl-(1–6C)alkyl, n is 0, 1 or 2; R² is hydroxy, halogeno,trifluoromethyl, cyano, mercapto, nitro, amino, carboxy,(1–6C)alkoxycarbonyl, (1–6C)alkyl, (2–6C)alkenyl, (2–6C)alkynyl,(1–6C)alkoxy, (1–6C)alkylamino or di-[(1–6C)alkyl]amino; R³ is hydrogen,halogeno, (1–6C)alkyl or (1–6C)alkoxy; q is 0, 1,2,3 or 4; and Q isaryl, optionally substituted with 1, 2 or 3 substituents selected fromhydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino,carboxy, carbamoyl, formyl, (1–6C)alkyl, (2–6C)alkenyl, (2–6C)alkynyl,(1–6C)alkoxy, (1–6C)alkylthio, (1–6C)alkylsulphinyl,(1–6C)alkylsulphonyl, (1–6C)alkylamino, di-[(1–6C)alkyl]amino,(1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, (2–6C)alkanoyloxy,(1–6C)alkanoylamino, N-(1–6C)alkylsulphamoyl,N,N-di-[(1–6C)alkyl]sulphamoyl, (1–6C)alkanesulphonylamino,N-(1–6C)alkyl(1–6C)alkanesulphonylamino, halogeno-(1–6C)alkyl,hydroxy-(1–6C)alkyl, (1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl,amino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl,di-[(1–6C)alkyl]amino-(1–6C)alkyl, carboxy-(1–6C)alkyl,(1–6C)alkoxycarbonyl-(1–6C)alkyl, carbamoyl-(1–6C)alkyl,N-(1–6C)alkylcarbamoyl(1–6C)alkyl,N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkyl, halogeno-(2–6C)alkoxy,hydroxy-(2–6C)alkoxy, (1–6C)alkoxy-(2–6C)alkoxy, cyano-(1–6C)alkoxy,carboxy-(1–6C)alkoxy, (1–6C)alkoxycarbonyl-(1–6C)alkoxy,carbamoyl-(1–6C)alkoxy, N-(1–6C)alkylcarbamoyl-(1–6C)alkoxy,N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkoxy, amino-(2–6C)alkoxy,(1–6C)alkylamino-(2–6C)alkoxy, di-[(1–6C)alkyl]amino(2–6C)alkoxy,halogeno-(2–6C)alkylamino, hydroxy-(2–6C)alkylamino,(1–6C)alkoxy-(2–6C)alkylamino, cyano-(l -6C)alkylamino,carboxy-(1–6C)alkylamino, (1–6C)alkoxycarbonyl-(1–6C)alkylamino,carbamoyl-(1–6C)alkylamino, N-(1–6C)alkylcarbamoyl-(1–6C)alkylamino,N,N-di-[(1–6C)alkyl]carbamoyl(1–6C)alkylamino, amino-(2–6C)alkylamino,(1–6C)alkylamino-(2–6C)alkylamino,di-[(1–6C)alkyl]amino-(2–6C)alkylamino,N-(1–6C)alkyl-halogeno-(1–6C)alkylamino,N-(1–6C)alkyl-hydroxy-(2–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkoxy(2–6C)alkylamino,N-(1–6C)alkyl-cyano-(1–6C)alkylamino,N-(1–6C)alkyl-carboxy(1–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkoxycarbonyl-(1–6C)alkylamino,N-(1–6C)alkyl-carbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-N-(1–6C)alkylcarbamoyl(1–6C)alkylamino,N-(1–6C)alkyl-N,N-di-[(1–6C)alkyl]carbamoyl-(1–6C)alkylamino,N-(1–6C)alkyl-amino-(2–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkylamino(2–6C)alkylamino,N-(1–6C)alkyl-di-[(1–6C)alkyl]amino-(2–6C)alkylamino,halogeno-(2–6C)alkanoylamino, hydroxy-(2–6C)alkanoylamino,(1–6C)alkoxy-(2–6C)alkanoylamino, cyano-(2–6C)alkanoylamino,carboxy-(2–6C)alkanoylamino, (1–6C)alkoxycarbonyl-(2–6C)alkanoylamino,carbamoyl-(2–6C)alkanoylamino,N-(1–6C)alkylcarbamoyl-(2–6C)alkanoylamino,N,N-di-[(1–6C)alkyl]carbamoyl-(2–6C)alkanoylamino,amino-(2–6C)alkanoylamino, (1–6C)alkylamino-(2–6C)alkanoylamino,di-[(1–6C)alkyl]amino-(2–6C)alkanoylamino, aryl, aryl-(1–6C)alkyl,aryl-(1–6C)alkoxy, aryloxy, arylamino, N-(1–6)alkyl-arylamino,aryl-(1–6C)alkylamino, N-(1–6C)alkyl-aryl-(1–6C)alkylamino, aroylamino,arylsulphonylamino, N-arylsulphamoyl, aryl-(2–6C)alkanoylamino and(1–3C)alkylenedioxy, and wherein any of the substituents on Q definedhereinbefore which comprises a CH₂ group which is attached to 2 carbonatoms or a CH₃ group which is attached to a carbon atom may optionallybear on each said CH₂ or CH₃ group a substituent selected from hydroxy,amino, (1–6C)alkoxy, (1–6C)alkylamino and di-[(1–6C)alkyl]amino, andwherein any aryl group in a substituent on Q may optionally bear 1 or 2substituents selected from hydroxy, halogeno, (1–6C)alkyl, (1–6C)alkoxy,carboxy, (1–6C)alkoxycarbonyl, N-(1–6C)alkylcarbamoyl,N,N-di-[(1–6C)alkyl]carbamoyl, (2–6C)alkanoyl, amino, (1–6C)alkylamino,di-[(1–6C)alkyl]amino, halogeno-(1–6C)alkyl, hydroxy-(1–6C)alkyl,(1–6C)alkoxy-(1–6C)alkyl, cyano-(1–6C)alkyl, amino-(1–6C)alkyl,(1–6C)alkylamino-(1–6C)alkyl, di-[(1–6C)alkyl]amino-(1–6C)alkyl, aryland aryl-(l -6C)alkyl; or a pharmaceutically-acceptable salt orin-vivo-cleavable ester formed on an available carboxy group thereof. 3.An amide derivative of the Formula Ia according to claim 1 wherein X is—NHCO— or —CONH—; R³ is hydrogen, methyl or ethyl; m is 1 or 2; at leastone R¹ is a piperazinyl group and any other R¹ group that is present isselected from hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano,methyl, ethyl, methoxy, ethoxy, amino, methylamino, ethylamino,dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl,dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy,2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy,3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy,3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino,3-aminopropylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino,3-methylaminopropylamino, 3-ethylaminopropylamino,2-dimethylaminoethylamino, 2-diethylaminoethylamino,3-dimethylaminopropylamino, 3-diethylaminopropylamino,N-(2-aminoethyl)-N-methylamino, N-(3-aminopropyl)-N-methylamino,N-(2-methylaminoethyl)-N-methylamino,N-(2-ethylaminoethyl)-N-methylamino,N-(3-methylaminopropyl)-N-methylamino,N-(3-ethylaminopropyl)-N-methylamino,N-(2-dimethylaminoethyl)-N-methylamino,N-(2-diethylaminoethyl)-N-methylamino,N-(3-dimethylaminopropyl)-N-methylamino andN-(3-diethylaminopropyl)-N-methylamino; n is 0 or 1; R² is fluoro,chloro, bromo, methyl or ethyl; q is 0; and Q is phenyl, indenyl,indanyl, tetrahydronaphthyl or fluorenyl, which optionally bears 1 or 2substituents selected from hydroxy, fluoro, chloro, trifluoromethyl,cyano, amino, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy,cyclopentyloxy, methylenedioxy, methylamino, ethylamino, dimethylamino,diethylamino, acetamido, propionamido, N-methylacetamido,methanesulphonamido, N-methylmethanesulphonamido, aminomethyl,methylaminomethyl, ethylaminomethyl, dimethylaminomethyl,diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy,2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy,3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy,3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy,2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy andphenyl, and wherein any phenyl group in a substituent on Q mayoptionally bear 1 or 2 substituents selected from fluoro, chloro, methyland methoxy; or a pharmaceutically-acceptable salt thereof.
 4. An amidederivative of the Formula Ib according to claim 2 wherein R³ is hydrogenor methyl; m is 1 and R’ is 4-methylpiperazin-1-yl; n is 0 or 1; R² ismethyl; q is 0; and Q is phenyl which bears 1 or 2 substituents selectedfrom fluoro, chloro, trifluoromethyl, methoxy, cyclopentyloxy andacetamido, or Q is 1-fluorenyl; or a pharmaceutically-acceptable saltthereof.
 5. An amide derivative of the Formula Ib according to claim 2wherein R³ is hydrogen or methyl; m is 1 and R’ is4-methylpiperazin-1-yl; n is 0 or 1; R² is 6-methyl; q is 0; and Q is1-fluorenyl or 3-acetamidophenyl; or a pharmaceutically-acceptable saltthereof.
 6. An amide derivative of the Formula Ib according to claim 2wherein R³ is hydrogen; m is 1 and R¹ is 4-methylpiperazin-1-yl; n is 0or 1; R² is 6-methyl or 6-fluoro; q is 0; and Q is 2-methoxyphenyl,3-ethoxyphenyl, 3-(1,1,2,2-tetrafluoroethoxy)phenyl,3,4-methylenedioxyphenyl, 3-acetamidophenyl or 3-(4-fluorophenyl)phenyl;or a pharmaceutically-acceptable salt thereof.
 7. An amide derivative ofthe Formula Ia according to claim 1, which is3-[5-(3-acetamidobenzamido)-2-methylphenyl]-6-(4-methylpiperazin-1-yl)3,4-dihydroquinazolin-4-one,or a pharmaceutically-acceptable salt thereof.
 8. A process for thepreparation of an amide derivative of the Formula Ia or Ib, or apharmaceutically-acceptable salt or in-vivo-cleavable ester formed on anavailable carboxy group thereof, according to claim 1 or claim 2 whichcomprises: (a) reacting an N-phenyl-2-aminobenzamide of the Formula II

with a carboxylic acid of the Formula III, or a reactive derivativethereof,

wherein variable groups are as defined in claim 1 and wherein anyfunctional group is protected if necessary, and: (i) removing anyprotecting groups; and (ii) optionally forming apharmaceutically-acceptable salt or in-vivo-cleavable ester formed on anavailable carboxy group; (b) reacting an aniline of the Formula X

with a carboxylic acid of the Formula VI, or a reactive derivativethereof,

under standard amide bond forming conditions, wherein variable groupsare as defined in claim 1 and wherein any functional group is protectedif necessary, and: (i) removing any protecting groups; and (ii)optionally forming a pharmaceutically-acceptable salt orin-vivo-cleavable ester formed on an available carboxy group; (c) forthe preparation of an amide derivative of the Formula Ia wherein R¹ or asubstituent on Q is (1–6C)alkoxy or substituted (1–6C)alkoxy,(1–6C)alkylthio, (1–6C)alkylamino, di-[(1–6C)alkyl]amino or substituted(1–6C)alkylamino, the alkylation, conveniently in the presence of asuitable base, of an amide derivative of the Formula Ia wherein R¹ or asubstituent on Q is hydroxy, mercapto or amino as appropriate; (d) forthe preparation of an amide derivative of the Formula Ia wherein asubstituent on Q is amino, (1–6C)alkylamino, di-[(1–6C)alkyl]amino,substituted (1–6C)alkylamino or substitutedN-(1–6C)alkyl-(2–6C)alkylamino, the reaction, conveniently in thepresence of a suitable base, of an amide derivative of the Formula Iawherein a substituent on Q is a suitable leaving group with anappropriate amine; (e) for the preparation of an amide derivative of theFormula Ia wherein R¹ or a substituent on Q is (1–6C)alkanoylamino orsubstituted (2–6C)alkanoylamino, the acylation of a compound of theFormula Ia wherein R¹ or a substituent on Q is amino; (f) for thepreparation of an amide derivative of the Formula Ia wherein R¹ or asubstituent on Q is (1–6C)alkanesulphonylamino, the reaction of acompound of the Formula Ia wherein R¹ or a substituent on Q is aminowith a (1–6C)alkanesulphonic acid, or an activated derivative thereof;(g) for the preparation of an amide derivative of the Formula Ia whereinR¹ or a substituent on Q is carboxy, carboxy-(1–6C)alkyl,carboxy-(1–6C)alkoxy, carboxy-(1–6C)alkylamino,N-(1–6C)alkyl-carboxy-(1–6C)alkylamino or carboxy-(2–6C)alkanoylamino,the cleavage of a compound of the Formula Ia wherein R¹ or a substituenton Q is (1–6C)alkoxycarbonyl, (1–6C)alkoxycarbonyl-(1–6C)alkyl,(1–6C)alkoxycarbonyl-(1–6C)alkoxy,(1–6C)alkoxycarbonyl-(1–6C)alkylamino,N-(1–6C)alkyl-(1–6C)alkoxycarbonyl-(1–6C)alkylamino or(1–6C)alkoxycarbonyl-(2–6C)alkanoylamino as appropriate; or (h) for thepreparation of an amide derivative of the Formula Ia wherein R¹ isamino-(1–6C)alkyl, (1–6C)alkylamino-(1–6C)alkyl ordi-[(1–6C)alkyl]amino-(1–6C)alkyl, the reaction, conveniently in thepresence of a suitable base, of a compound of the Formula XIII

wherein X, R², R³, n, q and Q have any of the meanings defined in claim1 and Z is a suitable leaving group with an appropriate amine orheterocycle.
 9. A pharmaceutical composition which comprises an amidederivative of the Formula Ia or Ib, or a pharmaceutically-acceptable orin-vivo-cleavable ester formed on an available carboxy group thereof, asdefined in any one of claims 1–3 and 5–8, in association with apharmaceutically-acceptable diluent or carrier.
 10. A method of treatingrheumatoid arthritis in a warm-blooded animal in need thereof, whichcomprises administering an effective amount of an amide derivative ofthe Formula Ia or Ib, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester formed on an available carboxy group thereof, asdefined in any one of claims 1–3 and 5–8.
 11. A method of treatingosteoarthritis in a warm-blooded animal in need thereof, which comprisesadministering an effective amount of an amide derivative of the FormulaIa or Ib, or a pharmaceutically-acceptable salt or in-vivo-cleavableester formed on an available carboxy group thereof, as defined in anyone of claims 1–3 and 5–8.
 12. A method of treating psoriasis in awarm-blooded animal in need thereof, which comprises administering aneffective amount of an amide derivative of the Formula Ia or Ib, or apharmaceutically-acceptable salt or in-vivo-cleavable ester formed on anavailable carboxy group thereof, as defined in any one of claims 1–3 and5–8.
 13. A method of treating chronic obstructive pulmonary disease in awarm-blooded animal in need thereof, which comprises administering aneffective amount of an amide derivative of the Formula Ia or Ib, or apharmaceutically-acceptable salt or in-vivo-cleavable ester formed on anavailable carboxy group thereof, as defined in any one of claims 1–3 and5–8.